PDE4 inhibitor (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

ABSTRACT

The present invention relates to PDE4 inhibitor (R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol including the crystalline monohydrate thereof.

FIELD OF THE INVENTION

The present invention relates to pharmaceutically active boroncontaining compounds that inhibit phosphodiesterase 4 (PDE4),pharmaceutical compositions containing these compounds, and the use ofthese compounds for treating or preventing diseases, conditions, ordisorders ameliorated by inhibition of PDE4.

BACKGROUND

Inflammation is a major component of numerous diseases and individualswith such diseases often exhibit high levels of inflammatory regulatorsthat include, but are not limited to, the following cytokines IL-1α,IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-12, IL-13, IL-17,IL-18, IL-23, IL-31, IL-33, TNF-α, IFN-α, IFN-β, and IFN-γ. Anon-limiting list of disease states that are directly associated withinflammatory cytokines include: atopic dermatitis wherein inflammatorycytokines induce inflammation; psoriasis wherein inflammatory cytokinesinduce dermatitis; arthritis wherein inflammatory cytokines can lead tolesions in the synovial membrane and destruction of joint cartilage andbone; fibrosis wherein inflammatory cytokines can attack traumatizedtissue; lupus wherein inflammatory cytokines can exacerbate the immunecomplex deposition and damage; allergy wherein inflammatory cytokinescan induce inflammation, production of IgE, and congestion; fibromyalgiawherein inflammatory cytokines are elevated in patients; and surgicalcomplications wherein inflammatory cytokines can avert healing.

Other diseases associated with chronic inflammation include: cancer;heart attack wherein chronic inflammation contributes to coronaryatherosclerosis; Alzheimer's disease wherein chronic inflammationnegatively effects brain cells; congestive heart failure wherein chronicinflammation causes heart muscle wasting; stroke wherein chronicinflammation promotes thromboembolic events; and aortic valve stenosiswherein chronic inflammation damages heart valves. Arteriosclerosis,osteoporosis, Parkinson's disease, bacterial infection, viral infection,inflammatory bowel disease including Crohn's disease and ulcerativecolitis, as well as multiple sclerosis (a typical autoimmuneinflammatory-related disease) are also related to inflammation. Currentmethods available for the treatment of such inflammatory diseases can beunsatisfactory due to a lack of sufficient efficacy and/or drug relatedside effects associated therein. Therefore a need exists for newtherapeutic methods that modulate inflammatory process involved in thediseases, conditions, and disorders, disclosed herein.

In particular, Atopic Dermatitis (AD) is an inflammatory skin diseasethat, typically, manifests during early childhood but can appear inadolescence or adulthood and follows either a chronic or arelapsing/remitting disease progression. AD patients display pruriticskin and show susceptibility to cutaneous secondary bacterial, viral andfungal infections. Patients with AD can also demonstrate a compromisedbarrier function that leads to activation of keratinocytes and otherimmune cells. A number of inflammatory cytokines are involved in thesymptoms characteristic of AD including, but not limited to, IL-1 IL-2,IL-3, IL-4, IL-5, IL-6, IL-12, IL-13, IL-17, IL-18, IL-22, IL-23, IL-31,IL-33, IL-36, and TNF-α. Inflammatory cytokines facilitate theproduction of various chemoattractants or chemokines which support therecruitment of leukocytes to the disease site. Chemokines thatcontribute to inflammation in AD patients include, but not limited to,CCL1, CCL2, CCL3, CCL4, CCL5, CCL11, CCL13, CCL17, CCL18, CCL20, CCL22,CCL26 and CCL27.

There are limited therapeutic options for the treatment of AD. Thetopical use of anti-inflammatory steroids has been utilized in ADtreatment particularly in the case of acute disease flares. The steroidssuppress the activation and proliferation of inflammatory cells as wellas keratinocytes and fibroblasts. However, steroids can cause adverselocal side effects that include, but are not restricted to, skinatrophy, telangiectasia (abnormal dilation of capillary vessels),epidermal barrier disturbance, striae, rosacea, acne, hypertrichosis,hypopigmentation, delayed wound healing and alterations in skinelasticity. Emollients including petrolatum and over-the-countermoisturizers have been used to reduce the use of topical steroids.Topical application of mevalonic acid and nicotinamide has been used toimprove the epidermal barrier permeability through the production ofcholesterol and ceramide. Topical calcineurin inhibitors (TCI) such astacrolimus and pimecrolimus have been used in the treatment of AD.Cyclosporine A (CyA) has been used as an immunosuppressant to inhibitcalcineurin phosphatase thereby leading to reduction in levels of IL-2and inhibition of T cell proliferation. Systemic treatment includehumanized monoclonal antibodies such as Omalizumab, Efalizumab andEtanercept, Dupilumab that target serum IgE, LFA-1, TNF-α, and IL-4rrespectively [Rahman, Inf. & All. 2011, 10, 486]. Additional eczema,skin and disease conditions include hand dermatitis, contact dermatitis,allergic contact dermatitis, irritant contact dermatitis,neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidroticeczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis,eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus,lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysisbullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis,acne, chronic spontaneous urticaria, chronic idiopathic urticaria,chronic physical urticaria, vogt-koyanagi-harada disease, suttonnevus/nevi, post inflammatory hypopigmentation, senile leukoderma,chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoidlupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, andhidradenitis suppurativa [Eyerich and Eyerich, J. Eur. Ac. Derm. Ven.,32, 692 (2018)].

Psoriasis is an immune-mediated chronic skin disease that exists inseveral different forms including plaque psoriasis, pustular psoriasis,nail psoriasis, flexural psoriasis, guttate psoriasis, psoriaticarthritis, erythrodermic psoriasis, and inverse psoriasis. Plaquepsoriasis (psoriasis vulgaris) is the most common form of psoriasis andtypically appears as patches of raised red skin covered by a flaky whitebuildup. Pustular psoriasis appears as raised bumps that are filled withnon-infectious pus (pustules). The skin under and surrounding pustulesis red and tender. Pustular psoriasis can be localized, commonly to thehands and feet, or generalized with widespread patches occurring on anypart of the body. Nail psoriasis produces a variety of changes in theappearance of finger and toe nails. These changes include discoloringunder the nail plate, pitting of the nails, lines going across thenails, thickening of the skin under the nail, and the loosening(onycholysis) and crumbling of the nail. Flexural psoriasis (inversepsoriasis) appears as smooth inflamed patches of skin. It occurs in skinfolds, particularly around the genitals (between the thigh and groin),the armpits, under an overweight stomach (pannus), and under the breasts(inframammary fold). It is aggravated by friction and sweat, and isvulnerable to fungal infections. Guttate psoriasis is characterized bynumerous small oval spots. These spots of psoriasis appear over largeareas of the body, such as the trunk, limbs, and scalp. Psoriaticarthritis involves joint and connective tissue inflammation. Psoriaticarthritis can affect any joint but is most common in the joints of thefingers and toes. Psoriatic arthritis can result in swelling of thefingers and toes known as dactylitis. Psoriatic arthritis can alsoaffect the hips, knees and spine (spondylitis). Erythrodermic psoriasisinvolves the widespread inflammation and exfoliation of the skin overmost of the body surface. It may be accompanied by severe itching,swelling and pain. It is often the result of an exacerbation of unstableplaque psoriasis, particularly following the abrupt withdrawal ofsystemic treatment. Current therapies available for treatment ofpsoriasis include topical treatment, phototherapy, and systemicapplications. The treatments are either cosmetically undesirable,inconvenient for long-term use, or have limited effectiveness.

Inflammatory Bowel Disease (IBD) describes a group of intestinaldisorders that involve inflammation of the digestive tract includingulcerative colitis and Crohn's disease. Ulcerative Colitis (UC) causesperiodic and chronic inflammation and ulcers in the lining of the largeintestine (colon). Crohn's disease (CD) is characterized by inflammationof the lining of the gastrointestinal tract and can penetrate intorelated tissues. Patients with IBD can exhibit diarrhea, abdominal pain,fatigue, and weight loss, and these conditions can be severe anddebilitating. As the symptoms vary depending on the level and durationof inflammation, an agent that modulates said inflammation would beuseful in treating IBD.

Phosphodiesterases (PDEs) represent a family of enzymes that catalyzethe hydrolysis of various cyclic nucleoside monophosphates includingcyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate(cGMP). PDEs regulate the level of cyclic nucleotides within cells andmaintain cyclic nucleotide homeostasis by hydrolyzing such cyclicmononucleotides resulting in termination of their messenger role. PDEenzymes can be grouped into families according to their specificitytoward hydrolysis of cAMP and/or cGMP, their sensitivity to regulationby calcium and calmodulin, and their selective inhibition by variouscompounds.

The PDE4 enzyme sub-family consists of four genes which produce 4isoforms of the PDE4 enzyme designated PDE4A, PDE4B, PDE4C, and PDE4D[Wang et al., Biochem. Biophys. Res. Comm., 234, 320 (1997)]. Inaddition, various splice variants of each PDE4 isoform have beenidentified. PDE4 isoenzymes specifically inactivate cAMP by catalyzingits hydrolysis to adenosine 5′-monophosphate (AMP). Regulation of cAMPactivity is important in many biological processes includinginflammation.

The compounds of the present invention inhibit phosphodiesterases,including PDE4, and modulate inflammatory cytokine levels and are,therefore, useful in treating inflammatory disorders such as atopicdermatitis, eczema, psoriasis, arthritis, asthma, fibrosis, lupus,allergy, fibromyalgia, wound healing, ulcerative colitis, Crohn'sdisease, inflammatory bowel disease, and inflammation resulting fromsurgical complications.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula (I) that inhibitPDE4 and are useful for treating or preventing disorders ameliorated byinhibition of PDE4 in humans,X—Y—Z  Formula (I)or a pharmaceutically acceptable salt thereof, wherein

X is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, or triazine,wherein each is optionally substituted with 1, 2, 3, 4, or 5substituents that are independently deuterium, (C₂-C₆)alkenyl,(C₂-C₆)alkenyloxy, (C₂-C₆)alkenylthio, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy-d₁₋₁₃, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl,(C₁-C₆)alkyl-d₁₋₁₃, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio,(C₂-C₆)alkynyl, (C₂-C₆)alkynyloxy, (C₂-C₆)alkynylthio, aryl,aryl(C₁-C₆)alkoxy, aryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkylthio, aryloxy,arylthio, carboxy, carboxy(C₁-C₆)alkoxy, carboxy(C₁-C₆)alkyl, cyano,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, C₃-C₈)cycloalkyl(C₁-C₆)alkylthio,(C₃-C₈)cycloalkyloxy, (C₃-C₈)cycloalkylthio, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkylthio, (5-6 membered)heteroaryl, (5-6membered)heteroaryl(C₁-C₆)alkoxy, (5-6 membered)heteroaryl(C₁-C₆)alkyl,(5-6 membered)heteroaryl(C₁-C₆)alkylthio, (5-6 membered)heteroaryloxy,(5-6 membered)heteroarylthio, (4-7 membered)heterocycle containing atleast one heteroatom independently selected from the group consisting ofO, N, and S, (4-7 membered)heterocycle(C₁-C₆)alkoxy, (4-7membered)heterocycle(C₁-C₆)alkyl, (4-7membered)heterocycle(C₁-C₆)alkylthio, (4-7 membered)heterocycleoxy, (4-7membered)heterocyclethio, hydroxy, hydroxy(C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, thio(C₁-C₆)alkyl, —NR_(A)R_(B),NR_(A)R_(B)(C₁-C₆)alkoxy, NR_(A)R_(B)(C₁-C₆)alkyl, or(NR_(A)R_(B))carbonyl; R_(A) and R_(B) are independently hydrogen,(C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; Y is phenyl, pyridine,pyrimidine, pyrazine, pyridazine, triazine, furan, thiophene, pyrrole,oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole,oxadiazole, thiadiazole, or triazole, wherein each is optionallysubstituted with 1, 2, or 3 substituents that are independentlydeuterium, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy-d₁₋₁₃,(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₃)alkyl,(C₁-C₃)alkyl-d₁₋₇, (C₁-C₆)alkyl, (C₁-C₆)alkyl-d₁₋₁₃,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio, carboxy, carboxy(C₁-C₆)alkoxy,carboxy(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,mercapto, nitro, —NR_(C)R_(D), NR_(C)R_(D)(C₁-C₆)alkoxy,NR_(C)R_(D)(C₁-C₆)alkyl, or (NR_(C)R_(D))carbonyl; R_(C) and R_(D) areindependently hydrogen, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; Z is

wherein B is boron; R₁₀ at each occurrence is independently H,deuterium, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₁-C₆)alkyl-d₁₋₁₃,(C₁-C₆)alkylthio(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, or thio(C₁-C₆)alkyl;R₁₁ at each occurrence is independently deuterium, (C₁-C₃)alkyl, or(C₁-C₃)alkyl-d₁; R₁₂ is independently H, (C₁-C₆)alkyl, orhydroxy(C₁-C₆)alkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0,1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, 5, or 6; and r is 0, 1, 2, 3, 4,5, 6 or 7.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (I) and at least onepharmaceutically acceptable excipient, diluent, or carrier.

In another embodiment, the present invention provides a method fortreating or preventing inflammatory diseases in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing inflammatory diseases in a mammal, particularly ahuman, comprising topically administering to the mammal or human, inneed of such treatment, a therapeutically effective amount of a compoundof Formula (I), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides the use of compoundsof Formula (I) in the manufacture of a medicament for treatinginflammatory diseases in a mammal, particularly a human.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an X-ray structure (ORTEP drawing) of crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 3).

FIG. 2 is an X-ray structure (ORTEP drawing) of crystalline (R)4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 4).

FIG. 3 is an X-ray structure (ORTEP drawing) of crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 5).

FIG. 4 is an X-ray structure (ORTEP drawing) of crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol(Example 19).

FIG. 5 is a powder X-ray diffraction analysis of crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 3).

FIG. 6 is a powder X-ray diffraction analysis of crystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 4).

FIG. 7 is a powder X-ray diffraction analysis of crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 5).

FIG. 8 is a powder X-ray diffraction analysis of crystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 10).

FIG. 9 is a powder X-ray diffraction analysis of crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol(Example 19).

FIG. 10 is a powder X-ray diffraction analysis of crystalline(4-methoxy-3-propoxyphenyl)boronic acid.

FIG. 11 is a powder X-ray diffraction analysis of crystalline3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine.

FIG. 12 is a powder X-ray diffraction analysis of crystalline3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine.

DETAILED DESCRIPTION OF THE INVENTION

In another embodiment, the present invention provides compounds ofFormula (I)X—Y—Z  Formula (I)or a pharmaceutically acceptable salt thereof, wherein X is phenyl,pyridine, or pyrimidine, wherein each is optionally substituted with 1,2, 3, 4, or 5 substituents that are independently deuterium,(C₂-C₆)alkenyl, (C₂-C₆)alkenyloxy, (C₂-C₆)alkenylthio, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy-d₁₋₁₃, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl,(C₁-C₆)alkyl-d₁₋₁₃, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio,(C₂-C₆)alkynyl, (C₂-C₆)alkynyloxy, (C₂-C₆)alkynylthio, aryl,aryl(C₁-C₆)alkoxy, aryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkylthio, aryloxy,arylthio, carboxy, carboxy(C₁-C₆)alkoxy, carboxy(C₁-C₆)alkyl, cyano,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, C₃-C₈)cycloalkyl(C₁-C₆)alkylthio,(C₃-C₈)cycloalkyloxy, (C₃-C₈)cycloalkylthio, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkylthio, (5-6 membered)heteroaryl, (5-6membered)heteroaryl(C₁-C₆)alkoxy, (5-6 membered)heteroaryl(C₁-C₆)alkyl,(5-6 membered)heteroaryl(C₁-C₆)alkylthio, (5-6 membered)heteroaryloxy,(5-6 membered)heteroarylthio, (4-7 membered)heterocycle containing atleast one heteroatom independently selected from the group consisting ofO, N, and S, (4-7 membered)heterocycle(C₁-C₆)alkoxy, (4-7membered)heterocycle(C₁-C₆)alkyl, (4-7membered)heterocycle(C₁-C₆)alkylthio, (4-7 membered)heterocycleoxy, (4-7membered)heterocyclethio, hydroxy, hydroxy(C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, thio(C₁-C₆)alkyl, —NR_(A)R_(B),NR_(A)R_(B)(C₁-C₆)alkoxy, NR_(A)R_(B)(C₁-C₆)alkyl, or(NR_(A)R_(B))carbonyl; R_(A) and R_(B) are independently hydrogen,(C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; Y is phenyl, pyridine,pyrimidine, pyrazine, pyridazine, thiazole, pyrazole, or thiadiazole,wherein each is optionally substituted with 1, 2, or 3 substituents thatare independently deuterium, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy-d₁₋₁₃,(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₃)alkyl,(C₁-C₃)alkyl-d₁₋₇, (C₁-C₆)alkyl, (C₁-C₆)alkyl-d₁₋₁₃,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio, carboxy, carboxy(C₁-C₆)alkoxy,carboxy(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,mercapto, nitro, —NR_(C)R_(D), NR_(C)R_(D)(C₁-C₆)alkoxy,NR_(C)R_(D)(C₁-C₆)alkyl, or (NR_(C)R_(D))carbonyl; R_(C) and R_(D) areindependently hydrogen, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; Z is asdefined in the Summary section herein; R₁₀ at each occurrence is H,deuterium, (C₁-C₆)alkyl, (C₁-C₆)alkyl-d₁₋₁₃, or hydroxy(C₁-C₆)alkyl; R₁₁at each occurrence is deuterium, methyl, or methyl-d₃; R₁₂ isindependently H, (C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl; m is 0, 1, 2, or3; n is 0 or 1; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, or 3; and r is0, 1, 2, 3, 4, 5, 6 or 7

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isphenyl, pyridine, or pyrimidine, wherein each is optionally substitutedwith 1, 2, or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (4-7 membered)heterocycleoxy, orhydroxy(C₁-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine,pyridazine, thiazole, pyrazole, or thiadiazole, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron; R₁₀ at each occurrence is H, methyl orhydroxymethyl; m is 1; and p is 1.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isphenyl, pyridine, or pyrimidine, wherein each is optionally substitutedwith 1, 2, or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (3-7membered)heterocycleoxy, orhydroxy(C₁-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine,pyridazine, thiazole, pyrazole, or thiadiazole, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isphenyl, pyridine, or pyrimidine, wherein each is optionally substitutedwith 1, 2, or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (4-7 membered)heterocycleoxy, orhydroxy(C₁-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine,pyridazine, thiazole, pyrazole, or thiadiazole, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isphenyl, pyridine, or pyrimidine, wherein each is optionally substitutedwith 1, 2, or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (4-7 membered)heterocycleoxy, orhydroxy(C₁-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine,pyridazine, thiazole, pyrazole, or thiadiazole, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isphenyl, pyridine, or pyrimidine, wherein each is optionally substitutedwith 1, 2, or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (4-7 membered)heterocycleoxy, orhydroxy(C₁-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine,pyridazine, thiazole, pyrazole, or thiadiazole, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron; R₁₀ at each occurrence is H, methyl orhydroxymethyl; p is 1; and r is 1.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isphenyl, pyridine, or pyrimidine, wherein each is optionally substitutedwith 1, 2, or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (4-7 membered)heterocycleoxy, orhydroxy(C₁-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine,pyridazine, thiazole, pyrazole, or thiadiazole, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron; R₁₀ at each occurrence is H, methyl orhydroxymethyl; R₁₂ is at each occurrence independently H, (C₁-C₆)alkyl,or hydroxy(C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isphenyl, pyridine, or pyrimidine, wherein each is optionally substitutedwith 1, 2, or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (4-7 membered)heterocycleoxy, orhydroxy(C₁-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine,pyridazine, thiazole, pyrazole, or thiadiazole, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron; R₁₂ is at each occurrence independently H,(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isphenyl, pyridine, or pyrimidine, wherein each is optionally substitutedwith 1, 2, or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (4-7 membered)heterocycleoxy, orhydroxy(C₁-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine,pyridazine, thiazole, pyrazole, or thiadiazole, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron; R₁₂ is at each occurrence independently H,(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isphenyl, pyridine, or pyrimidine, wherein each is optionally substitutedwith 1, 2, or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (4-7 membered)heterocycleoxy, orhydroxy(C₁-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine,pyridazine, thiazole, pyrazole, or thiadiazole, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron; and R₁₂ is at each occurrence independently H,(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isphenyl, pyridine, or pyrimidine, wherein each is optionally substitutedwith 1, 2, or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (4-7 membered)heterocycleoxy, orhydroxy(C₁-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine,pyridazine, thiazole, pyrazole, or thiadiazole, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron; R₁₀ at each occurrence is H, methyl orhydroxymethyl; R₁₁ at each occurrence is independently (C₁-C₃)alkyl; andn is 0, 1, 2, 3, or 4.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isphenyl, pyridine, or pyrimidine, wherein each is optionally substitutedwith 1, 2, or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (4-7 membered)heterocycleoxy, orhydroxy(C₁-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine,pyridazine, thiazole, pyrazole, or thiadiazole, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron; R₁₁ is methyl; and n is 0 or 1.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isphenyl, pyridine, or pyrimidine, wherein each is optionally substitutedwith 1, 2, or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (4-7 membered)heterocycleoxy, orhydroxy(C₁-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine,pyridazine, thiazole, pyrazole, or thiadiazole, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron; R₁₁ is methyl; and n is 0 or 1.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isphenyl, pyridine, or pyrimidine, wherein each is optionally substitutedwith 1, 2, or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (4-7 membered)heterocycleoxy, orhydroxy(C₁-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine,pyridazine, thiazole, pyrazole, or thiadiazole, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron; R is methyl; and n is 0 or 1.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isphenyl, pyridine, or pyrimidine, wherein each is optionally substitutedwith 1, 2, or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (4-7 membered)heterocycleoxy, orhydroxy(C₁-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine,pyridazine, thiazole, pyrazole, or thiadiazole, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron; R₁₀ at each occurrence is H, methyl orhydroxymethyl; R₁₁ at each occurrence is independently (C₁-C₃)alkyl; andq is 0, 1, 2, 3, 4, 5, or 6.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isphenyl, pyridine, or pyrimidine, wherein each is optionally substitutedwith 1, 2, or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (4-7 membered)heterocycleoxy, orhydroxy(C₁-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine,pyridazine, thiazole, pyrazole, or thiadiazole, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron; R₁₁ at each occurrence is methyl; and q is 0, 1, 2,or 3.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isphenyl, pyridine, or pyrimidine, wherein each is optionally substitutedwith 1, 2, or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (4-7 membered)heterocycleoxy, orhydroxy(C₁-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine,pyridazine, thiazole, pyrazole, or thiadiazole, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron; R₁₁ at each occurrence is methyl; and q is 0, 1, 2,or 3.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isphenyl, pyridine, or pyrimidine, wherein each is optionally substitutedwith 1, 2, or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyano, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (4-7 membered)heterocycleoxy, orhydroxy(C₁-C₆)alkoxy; Y is phenyl, pyridine, pyrimidine, pyrazine,pyridazine, thiazole, pyrazole, or thiadiazole, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron; R₁₁ at each occurrence is methyl; and q is 0, 1, 2,or 3.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X is

A₁ and A₂ are independently O or S; R₁, R₂, and R₅ are independently H,deuterium, cyano, halogen, or halo(C₁-C₆)alkyl; R₃ and R₄ areindependently H, (C₁-C₆)alkyl, (C₁-C₆)alkyl-d₁₋₁₃, (C₃-C₈)cycloalkyl,halo(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl; Y is

R₆, R₇, R₈, and R₉ are independently H, deuterium, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy-d₁₋₁₃, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₃)alkyl, (C₁-C₃)alkyl-d₁₋₇,(C₁-C₆)alkyl, (C₁-C₆)alkyl-d₁₋₁₃, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, carboxy(C₁-C₆)alkoxy, carboxy(C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(C)R_(D), NR_(C)R_(D)(C₁-C₆)alkoxy, NR_(C)R_(D)(C₁-C₆)alkyl, or(NR_(C)R_(D))carbonyl; R_(C) and R_(D) are independently hydrogen,(C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; Z is as defined in the Summarysection herein; R₁₀ at each occurrence is independently H, deuterium,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₁-C₆)alkyl-d₁₋₁₃,(C₁-C₆)alkylthio(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, or thio(C₁-C₆)alkyl;R₁₁ at each occurrence is independently (C₁-C₃)alkyl or(C₁-C₃)alkyl-d₁₇; R₁₂ is independently H, (C₁-C₆)alkyl, orhydroxy(C₁-C₆)alkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0,1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, 5, or 6; and r is 0, 1, 2, 3, 4,5, 6 or 7.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X is

R₁, R₂, and R₅ are independently H, cyano, halogen, or halo(C₁-C₆)alkyl;R₃ and R₄ are independently (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,halo(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl; Y is

R₆, R₇, R₈, and R₉ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is asdefined in the Summary section herein; R₁₀ at each occurrence isindependently H, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylthio(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, or thio(C₁-C₆)alkyl;R₁₁ at each occurrence is independently (C₁-C₃)alkyl; R₁₂ isindependently H, (C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl; m is 0, 1, 2, or3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4,5, or 6; and r is 0, 1, 2, 3, 4, 5, 6 or 7.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X is

R₁, R₂, and R₅ are independently H, cyano, halogen, or halo(C₁-C₆)alkyl;R₃ and R₄ are independently (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,halo(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl; Y is

R₆, R₇, R₈, and R₉ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; Z is

wherein B is boron; R₁₀ at each occurrence is independently H,(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl; m is 0, 1, 2, or 3; and p is 0, 1,2, 3, 4, or 5.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X is

R₁, R₂, and R₅ are independently H, cyano, halogen, or halo(C₁-C₆)alkyl;R₃ and R₄ are independently (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,halo(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl; Y is

R₆, R₇, R₈, and R₉ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; and Z is

wherein B is boron.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X is

R₁, R₂, and R₅ are independently H, cyano, halogen, or halo(C₁-C₆)alkyl;R₃ and R₄ are independently (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,halo(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl; Y is

R₆, R₇, R₈, and R₉ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; and Z is

wherein B is boron.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X is

R₁, R₂, and R₅ are independently H, cyano, halogen, or halo(C₁-C₆)alkyl;R₃ and R₄ are independently (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,halo(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl; Y is

R₆, R₇, R₈, and R₉ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl; and Z is

wherein B is boron.

In another embodiment, the present invention provides compounds ofFormula (IA)

or a pharmaceutically acceptable salt thereof, wherein B is boron; A₁and A₂ are independently O or S; R₁, R₂, and R₅ are independently H,deuterium, (C₂-C₆)alkenyl, (C₂-C₆)alkenyloxy, (C₂-C₆)alkenylthio,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy-d₁₋₁₃, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl,(C₁-C₆)alkyl-d₁₋₁₃, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio,(C₂-C₆)alkynyl, (C₂-C₆)alkynyloxy, (C₂-C₆)alkynylthio, aryl,aryl(C₁-C₆)alkoxy, aryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkylthio, aryloxy,arylthio, carboxy, carboxy(C₁-C₆)alkoxy, carboxy(C₁-C₆)alkyl, cyano,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, C₃-C₈)cycloalkyl(C₁-C₆)alkylthio,(C₃-C₈)cycloalkyloxy, (C₃-C₈)cycloalkylthio, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkylthio, (5-6 membered)heteroaryl, (5-6membered)heteroaryl(C₁-C₆)alkoxy, (5-6 membered)heteroaryl(C₁-C₆)alkyl,(5-6 membered)heteroaryl(C₁-C₆)alkylthio, (5-6 membered)heteroaryloxy,(5-6 membered)heteroarylthio, (4-7 membered)heterocycle containing atleast one heteroatom independently selected from the group consisting ofO, N, and S, (4-7 membered)heterocycle(C₁-C₆)alkoxy, (4-7membered)heterocycle(C₁-C₆)alkyl, (4-7membered)heterocycle(C₁-C₆)alkylthio, (4-7 membered)heterocycleoxy, (4-7membered)heterocyclethio, hydroxy, hydroxy(C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, thio(C₁-C₆)alkyl, —NR_(A)R_(B),NR_(A)R_(B)(C₁-C₆)alkoxy, NR_(A)R_(B)(C₁-C₆)alkyl, or(NR_(A)R_(B))carbonyl; R_(A) and R_(B) are independently hydrogen,(C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₃ and R₄ are independently H,deuterium, (C₁-C₃)alkyl, (C₁-C₃)alkyl-d₁₋₇, (C₁-C₆)alkyl,(C₁-C₆)alkyl-d₁₋₁₃, (C₃-C₈)cycloalkyl, halo(C₁-C₆)alkyl, orhydroxy(C₁-C₆)alkyl; R₆, R₇, and R₉ are independently, H, deuterium,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy-d₁₋₁₃, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₃)alkyl, (C₁-C₃)alkyl-d₁₋₇,(C₁-C₆)alkyl, (C₁-C₆)alkyl-d₁₋₁₃, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, carboxy(C₁-C₆)alkoxy, carboxy(C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(C)R_(D), NR_(C)R_(D)(C₁-C₆)alkoxy, NR_(C)R_(D)(C₁-C₆)alkyl, or(NR_(C)R_(D))carbonyl; R_(C) and R_(D) are independently hydrogen,(C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₁₀ at each occurrence isindependently deuterium, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₃)alkyl,(C₁-C₃)alkyl-d₁₋₇, (C₁-C₆)alkyl, (C₁-C₆)alkyl-d₁₋₁₃,(C₁-C₆)alkylthio(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, or thio(C₁-C₆)alkyl;and p is 0, 1, 2, 3, 4, or 5.

In another embodiment, the present invention provides compounds ofFormula (IA), or a pharmaceutically acceptable salt thereof, wherein Bis boron; A₁ and A₂ are O; R₁, R₂, and R₅ are independently H, cyano,halogen, or halo(C₁-C₆)alkyl; R₃ and R₄ are independently (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, halo(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl; R₆, R₇, andR₉ are independently, H, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl;R₁₀ is (C₁-C₃)alkyl, (C₁-C₆)alkyl or hydroxy(C₁-C₆)alkyl; and p is 0 or1.

In another embodiment, the present invention provides compounds ofFormula (IA), or a pharmaceutically acceptable salt thereof, wherein Bis boron; A and A₂ are O; R₁, R₂, and R₅ are H; R₃ and R₄ areindependently (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, halo(C₁-C₆)alkyl, orhydroxy(C₁-C₆)alkyl; R₆, R₇, and R₉ are independently H or (C₁-C₃)alkyl;R₁₀ is methyl; and p is 0, 1, or 2.

In another embodiment, the present invention provides compounds ofFormula (IA), or a pharmaceutically acceptable salt thereof, wherein Bis boron; A₁ and A₂ are O; R₁, R₂, and R₅ are H; R₃ and R₄ areindependently (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, halo(C₁-C₆)alkyl, orhydroxy(C₁-C₆)alkyl; R₆, R₇, and R₉ are independently H or (C₁-C₃)alkyl;and p is 0.

In another embodiment, the present invention provides compounds ofFormula (IA), or a pharmaceutically acceptable salt thereof, wherein Bis boron; A and A₂ are O; R₁, R₂, and R₅ are H; R₃ and R₄ areindependently (C₁-C₃)alkyl; R₆, R₇, and R₉ are independently H or(C₁-C₃)alkyl; and p is 0.

In another embodiment, the present invention provides compounds ofFormula (IA), or a pharmaceutically acceptable salt thereof, wherein Bis boron; A and A₂ are O; R₁, R₂, and R₅ are H; R₃ and R₄ areindependently (C₁-C₃)alkyl; R₆, R₇, and R₉ are H; and p is 0.

In another embodiment, the present invention provides compounds ofFormula (IB)

or a pharmaceutically acceptable salt thereof, wherein B is boron; A andA₂ are independently O or S; R₁, R₂, and R₅ are independently H,deuterium, (C₂-C₆)alkenyl, (C₂-C₆)alkenyloxy, (C₂-C₆)alkenylthio,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy-d₁₋₁₃, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl,(C₁-C₆)alkyl-d₁₋₁₃, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio,(C₂-C₆)alkynyl, (C₂-C₆)alkynyloxy, (C₂-C₆)alkynylthio, aryl,aryl(C₁-C₆)alkoxy, aryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkylthio, aryloxy,arylthio, carboxy, carboxy(C₁-C₆)alkoxy, carboxy(C₁-C₆)alkyl, cyano,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, C₃-C₈)cycloalkyl(C₁-C₆)alkylthio,(C₃-C₈)cycloalkyloxy, (C₃-C₈)cycloalkylthio, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkylthio, (5-6 membered)heteroaryl, (5-6membered)heteroaryl(C₁-C₆)alkoxy, (5-6 membered)heteroaryl(C₁-C₆)alkyl,(5-6 membered)heteroaryl(C₁-C₆)alkylthio, (5-6 membered)heteroaryloxy,(5-6 membered)heteroarylthio, (4-7 membered)heterocycle containing atleast one heteroatom independently selected from the group consisting ofO, N, and S, (4-7 membered)heterocycle(C₁-C₆)alkoxy, (4-7membered)heterocycle(C₁-C₆)alkyl, (4-7membered)heterocycle(C₁-C₆)alkylthio, (4-7 membered)heterocycleoxy, (4-7membered)heterocyclethio, hydroxy, hydroxy(C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, thio(C₁-C₆)alkyl, —NR_(A)R_(B),NR_(A)R_(B)(C₁-C₆)alkoxy, NR_(A)R_(B)(C₁-C₆)alkyl, or(NR_(A)R_(B))carbonyl; R_(A) and R_(B) are independently hydrogen,(C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₃ and R₄ are independently H,deuterium, (C₁-C₃)alkyl, (C₁-C₃)alkyl-d₁₋₇, (C₁-C₆)alkyl,(C₁-C₆)alkyl-d₁₋₁₃, (C₃-C₈)cycloalkyl, halo(C₁-C₆)alkyl, orhydroxy(C₁-C₆)alkyl; R₆, R₇, and R₉ are independently, H, deuterium,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy-d₁₋₁₃, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₃)alkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio, carboxy, carboxy(C₁-C₆)alkoxy,carboxy(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,mercapto, nitro, —NR_(C)R_(D), NR_(C)R_(D)(C₁-C₆)alkoxy,NR_(C)R_(D)(C₁-C₆)alkyl, or (NR_(C)R_(D))carbonyl; R_(C) and R_(D) areindependently hydrogen, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₁₀ ateach occurrence is independently deuterium, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₃)alkyl, (C₁-C₃)alkyl-d₁₋₇, (C₁-C₆)alkyl, (C₁-C₆)alkyl-d₁₋₁₃,(C₁-C₆)alkylthio(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, or thio(C₁-C₆)alkyl;and p is 0, 1, 2, 3, 4, or 5.

In another embodiment, the present invention provides compounds ofFormula (IB), or a pharmaceutically acceptable salt thereof, wherein Bis boron; A₁ and A₂ are O; R₁, R₂, and R₅ are independently H, cyano,halogen, or halo(C₁-C₆)alkyl; R₃ and R₄ are independently (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, halo(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl; R₆, R₇, andR₉ are independently, H, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl;R₁₀ is (C₁-C₃)alkyl, (C₁-C₆)alkyl or hydroxy(C₁-C₆)alkyl; and p is 0 or1.

In another embodiment, the present invention provides compounds ofFormula (IB), or a pharmaceutically acceptable salt thereof, wherein Bis boron; A and A₂ are O; R₁, R₂, and R₅ are H; R₃ and R₄ areindependently (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, halo(C₁-C₆)alkyl, orhydroxy(C₁-C₆)alkyl; R₆, R₇, and R₉ are independently H or (C₁-C₃)alkyl;R₁₀ is methyl; and p is 0, 1, or 2.

In another embodiment, the present invention provides compounds ofFormula (IB), or a pharmaceutically acceptable salt thereof, wherein Bis boron; A and A₂ are O; R₁, R₂, and R₅ are H; R₃ and R₄ areindependently (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, halo(C₁-C₆)alkyl, orhydroxy(C₁-C₆)alkyl; R₆, R₇, and R₉ are independently H or (C₁-C₃)alkyl;and p is 0.

In another embodiment, the present invention provides compounds ofFormula (IB), or a pharmaceutically acceptable salt thereof, wherein Bis boron; A and A₂ are O; R₁, R₂, and R₅ are H; R₃ and R₄ areindependently (C₁-C₃)alkyl; R₆, R₇, and R₉ are independently H or(C₁-C₃)alkyl; and p is 0.

In another embodiment, the present invention provides compounds ofFormula (IB), or a pharmaceutically acceptable salt thereof, wherein Bis boron; A₁ and A₂ are O; R₁, R₂, and R₅ are H; R₃ and R₄ areindependently (C₁-C₃)alkyl; R₆, R₇, and R₉ are H; and p is 0.

In another embodiment, the present invention provides compounds ofFormula (IC)

or a pharmaceutically acceptable salt thereof, wherein B is boron; A₁and A₂ are independently O or S; R₁, R₂, and R₅ are independently H,deuterium, (C₂-C₆)alkenyl, (C₂-C₆)alkenyloxy, (C₂-C₆)alkenylthio,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy-d₁₋₁₃, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl,(C₁-C₆)alkyl-d₁₋₁₃, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio,(C₂-C₆)alkynyl, (C₂-C₆)alkynyloxy, (C₂-C₆)alkynylthio, aryl,aryl(C₁-C₆)alkoxy, aryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkylthio, aryloxy,arylthio, carboxy, carboxy(C₁-C₆)alkoxy, carboxy(C₁-C₆)alkyl, cyano,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, C₃-C₈)cycloalkyl(C₁-C₆)alkylthio,(C₃-C₈)cycloalkyloxy, (C₃-C₈)cycloalkylthio, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkylthio, (5-6 membered)heteroaryl, (5-6membered)heteroaryl(C₁-C₆)alkoxy, (5-6 membered)heteroaryl(C₁-C₆)alkyl,(5-6 membered)heteroaryl(C₁-C₆)alkylthio, (5-6 membered)heteroaryloxy,(5-6 membered)heteroarylthio, (4-7 membered)heterocycle containing atleast one heteroatom independently selected from the group consisting ofO, N, and S, (4-7 membered)heterocycle(C₁-C₆)alkoxy, (4-7membered)heterocycle(C₁-C₆)alkyl, (4-7membered)heterocycle(C₁-C₆)alkylthio, (4-7 membered)heterocycleoxy, (4-7membered)heterocyclethio, hydroxy, hydroxy(C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, thio(C₁-C₆)alkyl, —NR_(A)R_(B),NR_(A)R_(B)(C₁-C₆)alkoxy, NR_(A)R_(B)(C₁-C₆)alkyl, or(NR_(A)R_(B))carbonyl; R_(A) and R_(B) are independently hydrogen,(C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₃ and R₄ are independently H,deuterium, (C₁-C₃)alkyl, (C₁-C₃)alkyl-d₁₋₇, (C₁-C₆)alkyl,(C₁-C₆)alkyl-d₁₋₁₃, (C₃-C₈)cycloalkyl, halo(C₁-C₆)alkyl, orhydroxy(C₁-C₆)alkyl; R₆, R₇, and R₉ are independently, H, deuterium,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy-d₁₋₁₃, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₃)alkyl, (C₁-C₃)alkyl-d₁₋₇,(C₁-C₆)alkyl, (C₁-C₆)alkyl-d₁₋₁₃, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, carboxy(C₁-C₆)alkoxy, carboxy(C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(C)R_(D), NR_(C)R_(D)(C₁-C₆)alkoxy, NR_(C)R_(D)(C₁-C₆)alkyl, or(NR_(C)R_(D))carbonyl; R_(C) and R_(D) are independently hydrogen,(C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₁₀ at each occurrence isindependently deuterium, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₃)alkyl,(C₁-C₃)alkyl-d₁₋₇, (C₁-C₆)alkyl, (C₁-C₆)alkyl-d₁₋₁₃,(C₁-C₆)alkylthio(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, or thio(C₁-C₆)alkyl;and p is 0, 1, 2, 3, 4, or 5.

In another embodiment, the present invention provides compounds ofFormula (IC), or a pharmaceutically acceptable salt thereof, wherein Bis boron; A and A₂ are O; R₁, R₂, and R₅ are independently H, cyano,halogen, or halo(C₁-C₆)alkyl; R₃ and R₄ are independently (C₁-C₆)alkyl,(C₁-C₈)cycloalkyl, halo(C₁-C₆)alkyl, or hydroxy(C₁-C₆)alkyl; R₆, R₇, andR₉ are independently, H, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, or hydroxy(C₁-C₆)alkyl;R₁₀ is (C₁-C₃)alkyl, (C₁-C₆)alkyl or hydroxy(C₁-C₆)alkyl; and p is 0 or1.

In another embodiment, the present invention provides compounds ofFormula (IC), or a pharmaceutically acceptable salt thereof, wherein Bis boron; A₁ and A₂ are O; R₁, R₂, and R₅ are H; R₃ and R₄ areindependently (C₁-C₆)alkyl, (C₁-C₈)cycloalkyl, halo(C₁-C₆)alkyl, orhydroxy(C₁-C₆)alkyl; R₆, R₇, and R₉ are independently H or (C₁-C₃)alkyl;R₁₀ is methyl; and p is 0, 1, or 2.

In another embodiment, the present invention provides compounds ofFormula (IC), or a pharmaceutically acceptable salt thereof, wherein Bis boron; A and A₂ are O; R₁, R₂, and R₅ are H; R₃ and R₄ areindependently (C₁-C₆)alkyl, (C₁-C₈)cycloalkyl, halo(C₁-C₆)alkyl, orhydroxy(C₁-C₆)alkyl; R₆, R₇, and R₉ are independently H or (C₁-C₃)alkyl;and p is 0.

In another embodiment, the present invention provides compounds ofFormula (IC), or a pharmaceutically acceptable salt thereof, wherein Bis boron; A and A₂ are O; R₁, R₂, and R₅ are H; R₃ and R₄ areindependently (C₁-C₃)alkyl; R₆, R₇, and R₉ are independently H or(C₁-C₃)alkyl; and p is 0.

In another embodiment, the present invention provides compounds ofFormula (IC), or a pharmaceutically acceptable salt thereof, wherein Bis boron; A and A₂ are O; R₁, R₂, and R₅ are H; R₃ and R₄ areindependently (C₁-C₃)alkyl; R₆, R₇, and R₉ are H; and p is 0.

In another embodiment, the present invention provides the followingcompounds: (R)4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S)4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R)4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S)4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R)4-(5-(3-isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-cyclopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-cyclopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(3-fluoro-5-methoxy-6-propoxy-[2,3′-bipyridin]-5′-yl)-1,2-oxaborolan-2-ol;(S)4-(3-fluoro-5-methoxy-6-propoxy-[2,3′-bipyridin]-5′-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R) 4-(6′-methoxy-5′-propoxy-[3,3′-bipyridin]-5-yl)-1,2-oxaborolan-2-ol;(S) 4-(6′-methoxy-5′-propoxy-[3,3′-bipyridin]-5-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(2-(4-methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol;(S)4-(2-(4-methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol;(R)4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(S)4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(R) 4-(6-(3-ethoxy-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol;(S) 4-(6-(3-ethoxy-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol;4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborol-2(5H)-ol; (R)4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborinan-2-ol; (S)4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborinan-2-ol; (R)4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborolan-2-ol;(S)4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborolan-2-ol;4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborol-2(5H)-ol;(R)4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-4-methyl-1,2-oxaborolan-2-ol;(S)4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-4-methyl-1,2-oxaborolan-2-ol;(R)4-(6-(4-methoxy-3-propoxyphenyl)pyridazin-4-yl)-5-methyl-1,2-oxaborolan-2-ol;(S)4-(6-(4-methoxy-3-propoxyphenyl)pyridazin-4-yl)-5-methyl-1,2-oxaborolan-2-ol;(R)4-(hydroxymethyl)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(hydroxymethyl)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(3′-(3-fluoropropoxy)-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(S)4-(3′-(3-fluoropropoxy)-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(R)3′-(2-hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-3-propoxy-[1,1′-biphenyl]-2-carbonitrile;(S)3′-(2-hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-3-propoxy-[1,1′-biphenyl]-2-carbonitrile;(R)3′-(2-hydroxy-2,5-dihydro-1,2-oxaborol-4-yl)-4-methoxy-3-propoxy-[1,1′-biphenyl]-2-carbonitrile;(S)3′-(2-hydroxy-2,5-dihydro-1,2-oxaborol-4-yl)-4-methoxy-3-propoxy-[1,1′-biphenyl]-2-carbonitrile;(R)4-(5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(6-(hydroxymethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(S)4-(6-(hydroxymethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(R) 4-(2-(3-ethoxy-4-methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol;(S) 4-(2-(3-ethoxy-4-methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol;(2R)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan-1-ol;(2S)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan-1-ol;(R) 4-(5-methoxy-6-propoxy-[2,3′-bipyridin]-5′-yl)-1,2-oxaborolan-2-ol:(S) 4-(5-methoxy-6-propoxy-[2,3′-bipyridin]-5′-yl)-1,2-oxaborolan-2-ol;(R)4-(3′-(2-fluoroethoxy)-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(S)4-(3′-(2-fluoroethoxy)-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(R)4-(4-(hydroxymethyl)-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(S)4-(4-(hydroxymethyl)-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(R)4-(6-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(S)4-(6-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(4-methoxy-3-(thietan-3-yloxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(4-methoxy-3-(thietan-3-yloxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(5-ethoxy-4-methoxy-2-methylphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(5-ethoxy-4-methoxy-2-methylphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-ethoxy-4-methoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-ethoxy-4-methoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(3′-isopropoxy-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(S)4-(3′-isopropoxy-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(R) 4-(3′-ethoxy-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(S) 4-(3′-ethoxy-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(4-methoxy-3-((tetrahydrothiophen-3-yl)oxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(4-methoxy-3-((tetrahydrothiophen-3-yl)oxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(2-fluoro-4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(2-fluoro-4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)-4-(6-((S)-1-hydroxyethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(R)-4-(6-((R)-1-hydroxyethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(S)-4-(6-((S)-1-hydroxyethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(S)-4-(6-((R)-1-hydroxyethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol(R)4-(5-(4-methoxy-3-propoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(4-methoxy-3-propoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol;(R)6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxy-2-propoxybenzonitrile;(S)6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxy-2-propoxybenzonitrile;(R) 4-(4′-methoxy-3′-propoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(S) 4-(4′-methoxy-3′-propoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(R)4-(2-(5-ethoxy-2-fluoro-4-methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol;(S)4-(2-(5-ethoxy-2-fluoro-4-methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol;(R)4-(3-(4-(cyclopentyloxy)-5-methoxypyrimidin-2-yl)phenyl)-1,2-oxaborolan-2-ol;(S)4-(3-(4-(cyclopentyloxy)-5-methoxypyrimidin-2-yl)phenyl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-ethoxy-4-methoxy-2-(trifluoromethyl)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-ethoxy-4-methoxy-2-(trifluoromethyl)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R) 4-(5-(3,4-diethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S)4-(5-(3,4-diethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R)4-(5-(3-(cyclopentyloxy)-4-(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-(cyclopentyloxy)-4-(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(2-(4-methoxy-3-propoxyphenyl)-6-(methoxymethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(S)4-(2-(4-methoxy-3-propoxyphenyl)-6-(methoxymethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(R) 4-(5-(4-ethoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S) 4-(5-(4-ethoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(2-fluoro-3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(2-fluoro-3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(4′-methoxy-3′-(pentyloxy)-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(S)4-(4′-methoxy-3′-(pentyloxy)-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(4-(methylthio)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(4-(methylthio)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R) 4-(6-(4-methoxy-3-propoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol;(S) 4-(6-(4-methoxy-3-propoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol;(R)4-(2′-fluoro-4′-methoxy-3′-propoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(S)4-(2′-fluoro-4′-methoxy-3′-propoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(R)3′-(2-hydroxy-1,2-oxaborolan-4-yl)-4,5-dimethoxy-[1,1′-biphenyl]-3-carbonitrile;(S)3′-(2-hydroxy-1,2-oxaborolan-4-yl)-4,5-dimethoxy-[1,1′-biphenyl]-3-carbonitrile;(R)3-ethoxy-5-(5-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-3-yl)-2-methoxybenzonitrile;(S)3-ethoxy-5-(5-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-3-yl)-2-methoxybenzonitrile;4-(3-(6-ethoxy-5-methoxypyridin-2-yl)phenyl)-1,2-oxaborol-2(5H)-ol; (R)4-(3-(6-ethoxy-5-methoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (S)4-(3-(6-ethoxy-5-methoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (R)4-(3-(4,5-dimethoxypyrimidin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (S)4-(3-(4,5-dimethoxypyrimidin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (R)4-(6-(3-(cyclopentyloxy)-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol;(S)4-(6-(3-(cyclopentyloxy)-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol;(R) 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(S) 4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;4-(3′-(cyclopentyloxy)-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborol-2(5H)-ol;(R)4-(3′-(cyclopentyloxy)-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(S)4-(3′-(cyclopentyloxy)-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol(R)4-(6-(3-(cyclopentyloxy)-4-methoxyphenyl)-5-fluoropyridin-2-yl)-1,2-oxaborolan-2-ol;(S)4-(6-(3-(cyclopentyloxy)-4-methoxyphenyl)-5-fluoropyridin-2-yl)-1,2-oxaborolan-2-ol;(R)4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)-6-methoxypyrimidin-4-yl)-1,2-oxaborolan-2-ol;(S)4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)-6-methoxypyrimidin-4-yl)-1,2-oxaborolan-2-ol;(R) ethyl2-(6-(2-hydroxy-1,2-oxaborolan-4-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate;(S) ethyl2-(6-(2-hydroxy-1,2-oxaborolan-4-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate;(R)2-(6-(2-hydroxy-1,2-oxaborolan-4-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)aceticacid; (S)2-(6-(2-hydroxy-1,2-oxaborolan-4-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)aceticacid; (R)4-(5-fluoro-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(S)4-(5-fluoro-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(R) 4-(6-(4-methoxy-3-propoxyphenyl)pyridazin-4-yl)-1,2-oxaborolan-2-ol;(S) 4-(6-(4-methoxy-3-propoxyphenyl)pyridazin-4-yl)-1,2-oxaborolan-2-ol;(R)4-(4-(difluoromethyl)-5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(4-(difluoromethyl)-5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-ethoxy-4-(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-ethoxy-4-(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R) 4-(5-(3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (S)4-(5-(3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol; (R)4-(5-(4-methoxy-3-propoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(4-methoxy-3-propoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(2′-fluoro-4′,5′-dimethoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(S)4-(2′-fluoro-4′,5′-dimethoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(R)2-ethoxy-6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxybenzonitrile;(S)2-ethoxy-6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxybenzonitrile;(R) 4-(3-(5,6-dimethoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (S)4-(3-(5,6-dimethoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (R)6-(5-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-3-yl)-2,3-dimethoxybenzonitrile;(S)6-(5-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-3-yl)-2,3-dimethoxybenzonitrile;(R)4-(2-(2-fluoro-4-methoxy-5-propoxyphenyl)-6-(hydroxymethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(S)4-(2-(2-fluoro-4-methoxy-5-propoxyphenyl)-6-(hydroxymethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;4-(3-(5-methoxy-6-propoxypyridin-2-yl)phenyl)-1,2-oxaborol-2(5H)-ol; (R)4-(3-(5-methoxy-6-propoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (S)4-(3-(5-methoxy-6-propoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (R)4-(3′,4′,5-trimethoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S)4-(3′,4′,5-trimethoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (R)4-(6-(4-methoxy-3-propoxyphenyl)-4-methylpyridin-2-yl)-1,2-oxaborolan-2-ol;(S)4-(6-(4-methoxy-3-propoxyphenyl)-4-methylpyridin-2-yl)-1,2-oxaborolan-2-ol;(R) 4-(2-(3,4-dimethoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol; (S)4-(2-(3,4-dimethoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol; (R)4-(3-(5,6-dimethoxypyridin-3-yl)phenyl)-1,2-oxaborolan-2-ol; (S)4-(3-(5,6-dimethoxypyridin-3-yl)phenyl)-1,2-oxaborolan-2-ol; (R)4-(6-(2-fluoro-3,4-dimethoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(S)4-(6-(2-fluoro-3,4-dimethoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-ethoxy-2,6-difluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-ethoxy-2,6-difluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(3′-(cyclopropylmethoxy)-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(S)4-(3′-(cyclopropylmethoxy)-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(R)4-(3′-ethoxy-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(S)4-(3′-ethoxy-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(2,4-dimethoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(2,4-dimethoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(4-methoxy-3-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(4-methoxy-3-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-ethylpyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-ethoxy-4-methoxyphenyl)-6-ethylpyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(3′-ethoxy-4′-(methylthio)-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(S)4-(3′-ethoxy-4′-(methylthio)-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R) 4-(3-(4,5-dimethoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (S)4-(3-(4,5-dimethoxypyridin-2-yl)phenyl)-1,2-oxaborolan-2-ol; (R)4-(4-(3-(cyclopentyloxy)-4-methoxyphenyl)-6-methoxypyrimidin-2-yl)-1,2-oxaborolan-2-ol;(S)4-(4-(3-(cyclopentyloxy)-4-methoxyphenyl)-6-methoxypyrimidin-2-yl)-1,2-oxaborolan-2-ol;(R)3′-(2-hydroxy-1,2-oxaborolan-4-yl)-3,4-dimethoxy-[1,1′-biphenyl]-2-carbonitrile;(S)3′-(2-hydroxy-1,2-oxaborolan-4-yl)-3,4-dimethoxy-[1,1′-biphenyl]-2-carbonitrile;(R) 4-(5-methoxy-4-propoxy-[2,3′-bipyridin]-5′-yl)-1,2-oxaborolan-2-ol;(S) 4-(5-methoxy-4-propoxy-[2,3′-bipyridin]-5′-yl)-1,2-oxaborolan-2-ol;(R)4-(2-(hydroxymethyl)-6-(4-methoxy-3-propoxyphenyl)pyridin-4-yl)-1,2-oxaborolan-2-ol;(S)4-(2-(hydroxymethyl)-6-(4-methoxy-3-propoxyphenyl)pyridin-4-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-cyclopropoxy-4-methoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-cyclopropoxy-4-methoxyphenyl)-1,2,4-thiadiazol-3-yl)-1,2-oxaborolan-2-ol;(R) 4-(4′-ethoxy-3′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(S) 4-(4′-ethoxy-3′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(R)4-(3′-isobutoxy-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(S)4-(3′-isobutoxy-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(R)4-(3′-cyclobutoxy-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol:(S)4-(3′-cyclobutoxy-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(R)4-(2-(3-ethoxy-4-methoxyphenyl)-6-methoxypyrimidin-4-yl)-1,2-oxaborolan-2-ol;(S)4-(2-(3-ethoxy-4-methoxyphenyl)-6-methoxypyrimidin-4-yl)-1,2-oxaborolan-2-ol;(R) 4-(5-(4-ethoxy-3-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S) 4-(5-(4-ethoxy-3-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)3-ethoxy-3′-(2-hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-[1,1′-biphenyl]-2-carbonitrile;(S)3-ethoxy-3′-(2-hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-[1,1′-biphenyl]-2-carbonitrile;(R)4-(6-(2-hydroxyethoxy)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(S)4-(6-(2-hydroxyethoxy)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(R) 4-(6-(3,4-dimethoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (S)4-(6-(3,4-dimethoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; (R)4-(4-(hydroxymethyl)-6-(4-methoxy-3-propoxyphenyl)pyrimidin-2-yl)-1,2-oxaborolan-2-ol;(S)4-(4-(hydroxymethyl)-6-(4-methoxy-3-propoxyphenyl)pyrimidin-2-yl)-1,2-oxaborolan-2-ol;(R)4-(6-(3-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(S)4-(6-(3-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(R)4-(1-(4-methoxy-3-propoxyphenyl)-1H-pyrazol-3-yl)-1,2-oxaborolan-2-ol;(S)4-(1-(4-methoxy-3-propoxyphenyl)-1H-pyrazol-3-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-methoxy-4-(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-methoxy-4-(methylthio)phenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(6-(3-ethoxy-4-(methylthio)phenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(S)4-(6-(3-ethoxy-4-(methylthio)phenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(3-ethoxy-4-methoxyphenyl)-4,6-dimethylpyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(3-ethoxy-4-methoxyphenyl)-4,6-dimethylpyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(3′-methoxy-4′-(methylthio)-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(S)4-(3′-methoxy-4′-(methylthio)-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(R)4-(3′,4′-dimethoxy-5-methyl-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(S)4-(3′,4′-dimethoxy-5-methyl-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(R)4-(2′-fluoro-3′,4′-dimethoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(S)4-(2′-fluoro-3′,4′-dimethoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol;(R)4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-4-yl)-1,2-oxaborolan-2-ol;(S)4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)pyridin-4-yl)-1,2-oxaborolan-2-ol;(R) 4-(2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(S) 4-(2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(R)4-(6-(2-fluoro-4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(S)4-(6-(2-fluoro-4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(R)4-(6-(2-fluoro-4-methoxy-3-propoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol;(S)4-(6-(2-fluoro-4-methoxy-3-propoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol;(R)4-(5-(4-ethoxy-2-fluoro-3-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(S)4-(5-(4-ethoxy-2-fluoro-3-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol;(R)4-(6′-methoxy-2-methyl-5′-propoxy-[3,3′-bipyridin]-5-yl)-1,2-oxaborolan-2-ol;(S)4-(6′-methoxy-2-methyl-5′-propoxy-[3,3′-bipyridin]-5-yl)-1,2-oxaborolan-2-ol;(R)4-(6-(3-ethoxy-4-methoxyphenyl)-4-(trifluoromethyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(S)4-(6-(3-ethoxy-4-methoxyphenyl)-4-(trifluoromethyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(R)4-(6-ethoxy-2-(3-ethoxy-4-methoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(S)4-(6-ethoxy-2-(3-ethoxy-4-methoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(R)4-(6-methoxy-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(S)4-(6-methoxy-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol;(R)2-(cyclopentyloxy)-6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxybenzonitrile;(S)2-(cyclopentyloxy)-6-(6-(2-hydroxy-1,2-oxaborolan-4-yl)pyridin-2-yl)-3-methoxybenzonitrile;4-(2-(3,4-dimethoxyphenyl)pyridin-4-yl)-1,2-oxaborol-2(5H)-ol;4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborol-2(5H)-ol; (R)4-(3-fluoro-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(S)4-(3-fluoro-6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol;(R)4-(5-methoxy-2′-methyl-6-propoxy-[2,3′-bipyridin]-5′-yl)-1,2-oxaborolan-2-ol;(S)4-(5-methoxy-2′-methyl-6-propoxy-[2,3′-bipyridin]-5′-yl)-1,2-oxaborolan-2-ol;(R) 4-(3′,4′-dimethoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (S)4-(3′,4′-dimethoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol; (R)4-(6-(3-ethoxy-4-methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; and(S) 4-(6-(3-ethoxy-4-methoxyphenyl)pyridin-2-yl)-1,2-oxaborolan-2-ol; ora pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (I), Formula (IA), Formula(IB), or Formula (IC), or a pharmaceutically acceptable salt thereof,and at least one pharmaceutically acceptable excipient, diluent, orcarrier.

In another embodiment, the present invention provides a method fortreating or preventing an inflammatory disease in a human comprisingadministering to the human in need of such treatment a therapeuticallyeffective amount of a compound of Formula (I), Formula (IA), Formula(IB), or Formula (IC), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing an inflammatory disease in a human comprisingtopically administering to the human in need of such treatment atherapeutically effective amount of a compound of Formula (I), Formula(IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptablesalt thereof, in the form of a transdermal patch, an ointment, a lotion,a cream, or a gel.

In another embodiment, the present invention provides a method fortreating or preventing atopic dermatitis, hand dermatitis, contactdermatitis, allergic contact dermatitis, irritant contact dermatitis,neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidroticeczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis,eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus,lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysisbullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis,acne, chronic spontaneous urticaria, chronic idiopathic urticaria,chronic physical urticaria, vogt-koyanagi-harada disease, suttonnevus/nevi, post inflammatory hypopigmentation, senile leukoderma,chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoidlupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome,hidradenitis suppurativa, psoriasis, plaque psoriasis, pustularpsoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis,psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in ahuman comprising administering to the human in need of such treatment atherapeutically effective amount of a compound of Formula (I), Formula(IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a method fortreating or preventing atopic dermatitis, hand dermatitis, contactdermatitis, allergic contact dermatitis, irritant contact dermatitis,neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidroticeczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis,eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus,lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysisbullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis,acne, cutaneous lupus erythematosus, discoid lupus, palmoplantarpustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa,psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis,flexural psoriasis, guttate psoriasis, psoriatic arthritis,erythrodermic psoriasis, or inverse psoriasis in a human comprisingtopically administering to the human in need of such treatment atherapeutically effective amount of a compound of Formula (I), Formula(IA), Formula (IB), or Formula (IC), or a pharmaceutically acceptablesalt thereof, in the form of a transdermal patch, an ointment, a lotion,a cream, or a gel.

In another embodiment, the present invention provides a method fortreating or preventing arthritis, asthma, fibrosis, lupus, allergy,fibromyalgia, wound healing, or inflammation resulting from surgicalcomplications in a human comprising administering to the human in needof such treatment a therapeutically effective amount of a compound ofFormula (I), Formula (IA), Formula (IB), or Formula (IC), or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing arthritis, asthma, fibrosis, lupus, allergy,fibromyalgia, wound healing, or inflammation resulting from surgicalcomplications in a human comprising topically administering to the humanin need of such treatment a therapeutically effective amount of acompound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), ora pharmaceutically acceptable salt thereof in the form of a transdermalpatch, an ointment, a lotion, a cream, or a gel.

In another embodiment, the present invention provides a method fortreating or preventing inflammatory bowel disease, ulcerative colitis,or Crohn's disease in a human comprising administering to the human inneed of such treatment a therapeutically effective amount of a compoundof Formula (I), Formula (IA), Formula (IB), or Formula (IC), or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides the use of acompound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), ora pharmaceutically acceptable salt thereof, in the manufacture of amedicament for treating an inflammatory disease in a human.

In another embodiment, the present invention provides the use of acompound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), ora pharmaceutically acceptable salt thereof, in the manufacture of amedicament for treating atopic dermatitis, hand dermatitis, contactdermatitis, allergic contact dermatitis, irritant contact dermatitis,neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidroticeczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis,eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus,lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysisbullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis,acne, chronic spontaneous urticaria, chronic idiopathic urticaria,chronic physical urticaria, vogt-koyanagi-harada disease, suttonnevus/nevi, post inflammatory hypopigmentation, senile leukoderma,chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoidlupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome,hidradenitis suppurativa, psoriasis, plaque psoriasis, pustularpsoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis,psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in ahuman.

In another embodiment, the present invention provides the use of acompound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), ora pharmaceutically acceptable salt thereof, in the manufacture of amedicament for treating arthritis, asthma, fibrosis, lupus, allergy,fibromyalgia, wound healing, or inflammation resulting from surgicalcomplications in a human.

In another embodiment, the present invention provides the use of acompound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), ora pharmaceutically acceptable salt thereof, in the manufacture of amedicament for treating inflammatory bowel disease, ulcerative colitis,or Crohn's disease in a human.

In another embodiment, the present invention provides crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks10.5±0.2, 18.3±0.2, and 24.9±0.2 degrees two theta.

In another embodiment, the present invention provides crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks10.5±0.2, 12.3±0.2, 13.5±0.2, 15.8±0.2, 16.0±0.2, 18.3±0.2, and 24.9±0.2degrees two theta.

In another embodiment, the present invention provides crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks10.5±0.2, 12.3±0.2, 13.5±0.2, 15.8±0.2, 16.0±0.2, 18.3±0.2, 21.5±0.2,22.9±0.2, 24.4±0.2, 24.9±0.2, 25.4±0.2, 26.5±0.2, 27.80.2, and 30.2±0.2degrees two theta.

In another embodiment, the present invention provides crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising 3 to 10diffraction peaks listed in Table 7.

In another embodiment, the present invention provides crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising the diffractionpeaks listed in Table 7.

In another embodiment, the present invention provides crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern as depicted in FIG. 5.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol andat least one pharmaceutically acceptable excipient, diluent, or carrier.

In another embodiment, the present invention provides a method fortreating or preventing an inflammatory disease in a human comprisingadministering to the human in need of such treatment a therapeuticallyeffective amount of crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method fortreating or preventing atopic dermatitis, hand dermatitis, contactdermatitis, allergic contact dermatitis, irritant contact dermatitis,neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidroticeczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis,eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus,lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysisbullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis,acne, chronic spontaneous urticaria, chronic idiopathic urticaria,chronic physical urticaria, vogt-koyanagi-harada disease, suttonnevus/nevi, post inflammatory hypopigmentation, senile leukoderma,chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoidlupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome,hidradenitis suppurativa, psoriasis, plaque psoriasis, pustularpsoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis,psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in ahuman comprising administering to the human in need of such treatment atherapeutically effective amount of crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method fortreating or preventing atopic dermatitis, hand dermatitis, contactdermatitis, allergic contact dermatitis, irritant contact dermatitis,neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidroticeczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis,eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus,lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysisbullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis,acne, chronic spontaneous urticaria, chronic idiopathic urticaria,chronic physical urticaria, vogt-koyanagi-harada disease, suttonnevus/nevi, post inflammatory hypopigmentation, senile leukoderma,chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoidlupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome,hidradenitis suppurativa, psoriasis, plaque psoriasis, pustularpsoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis,psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in ahuman comprising topically administering to the human in need of suchtreatment a therapeutically effective amount of crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe form of a transdermal patch, an ointment, a lotion, a cream, or agel.

In another embodiment, the present invention provides a method fortreating or preventing an arthritis, asthma, fibrosis, lupus, allergy,fibromyalgia, wound healing, or inflammation resulting from surgicalcomplications in a human comprising administering to the human in needof such treatment a therapeutically effective amount of crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method fortreating or preventing an arthritis, asthma, fibrosis, lupus, allergy,fibromyalgia, wound healing, or inflammation resulting from surgicalcomplications in a human comprising topically administering to the humanin need of such treatment a therapeutically effective amount ofcrystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe form of a transdermal patch, an ointment, a lotion, a cream, or agel..

In another embodiment, the present invention provides a method fortreating or preventing inflammatory bowel disease, ulcerative colitis,or Crohn's disease in a human comprising administering to the human inneed of such treatment a therapeutically effective amount of crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides the use ofcrystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe manufacture of a medicament for treating an inflammatory disease ina human.

In another embodiment, the present invention provides the use ofcrystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe manufacture of a medicament for treating atopic dermatitis, handdermatitis, contact dermatitis, allergic contact dermatitis, irritantcontact dermatitis, neurodermatitis, perioral dermatitis, stasisdermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis,seborrheic dermatitis, eyelid dermatitis, diaper dermatitis,dermatomyositis, lichen planus, lichen sclerosis, alopecia areata,vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasisalba, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria,chronic idiopathic urticaria, chronic physical urticaria,vogt-koyanagi-harada disease, sutton nevus/nevi, post inflammatoryhypopigmentation, senile leukoderma, chemical/drug-induced leukoderma,cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis,pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis,plaque psoriasis, pustular psoriasis, nail psoriasis, flexuralpsoriasis, guttate psoriasis, psoriatic arthritis, erythrodermicpsoriasis, or inverse psoriasis in a human.

In another embodiment, the present invention provides the use ofcrystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe manufacture of a medicament for treating arthritis, asthma,fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammationresulting from surgical complications in a human.

In another embodiment, the present invention provides the use ofcrystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe manufacture of a medicament for treating inflammatory bowel disease,ulcerative colitis, or Crohn's disease in a human.

In another embodiment, the present invention provides crystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides crystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks11.0±0.2, 22.9±0.2, and 25.1±0.2 degrees two theta.

In another embodiment, the present invention provides crystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks11.0±0.2, 11.4±0.2, 18.8±0.2, 22.9±0.2, 25.1±0.2, and 26.4±0.2 degreestwo theta.

In another embodiment, the present invention provides crystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks11.0±0.2, 11.4±0.2, 13.2 0.2, 15.1±0.2, 18.8±0.2, 21.3±0.2, 22.9±0.2,25.1±0.2, and 26.4±0.2 degrees two theta.

In another embodiment, the present invention provides crystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks11.0±0.2, 11.4±0.2, 13.2 0.2, 14.5±0.2, 15.1±0.2, 15.6±0.2, 15.9±0.2,17.7±0.2, 18.8±0.2, 19.4±0.2, 19.7±0.2, 20.5±0.2, 21.3±0.2, and22.9±0.2, degrees two theta.

In another embodiment, the present invention provides crystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks11.0±0.2, 11.4±0.2, 13.2 0.2, 14.5±0.2, 15.1±0.2, 15.6±0.2, 15.9±0.2,17.7±0.2, 18.8±0.2, 19.4±0.2, 19.7±0.2, 20.5±0.2, 21.3±0.2, 22.9±0.2,25.1±0.2, 25.9±0.2, 26.4±0.2, 27.5±0.2, and 28.4±0.2 degrees two theta.

In another embodiment, the present invention provides crystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising 3 to 10diffraction peaks listed in Table 8.

In another embodiment, the present invention provides crystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising the diffractionpeaks listed in Table 8.

In another embodiment, the present invention provides crystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern as depicted in FIG. 6.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising crystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-oland at least one pharmaceutically acceptable excipient, diluent, orcarrier.

In another embodiment, the present invention provides a method fortreating or preventing an inflammatory disease in a human comprisingadministering to the human in need of such treatment a therapeuticallyeffective amount of crystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method fortreating or preventing atopic dermatitis, hand dermatitis, contactdermatitis, allergic contact dermatitis, irritant contact dermatitis,neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidroticeczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis,eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus,lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysisbullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis,acne, chronic spontaneous urticaria, chronic idiopathic urticaria,chronic physical urticaria, vogt-koyanagi-harada disease, suttonnevus/nevi, post inflammatory hypopigmentation, senile leukoderma,chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoidlupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome,hidradenitis suppurativa, psoriasis, plaque psoriasis, pustularpsoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis,psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in ahuman comprising administering to the human in need of such treatment atherapeutically effective amount of crystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method fortreating or preventing atopic dermatitis, hand dermatitis, contactdermatitis, allergic contact dermatitis, irritant contact dermatitis,neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidroticeczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis,eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus,lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysisbullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis,acne, chronic spontaneous urticaria, chronic idiopathic urticaria,chronic physical urticaria, vogt-koyanagi-harada disease, suttonnevus/nevi, post inflammatory hypopigmentation, senile leukoderma,chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoidlupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome,hidradenitis suppurativa, psoriasis, plaque psoriasis, pustularpsoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis,psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in ahuman comprising topically administering to the human in need of suchtreatment a therapeutically effective amount of crystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe form of a transdermal patch, an ointment, a lotion, a cream, or agel.

In another embodiment, the present invention provides a method fortreating or preventing an arthritis, asthma, fibrosis, lupus, allergy,fibromyalgia, wound healing, or inflammation resulting from surgicalcomplications in a human comprising administering to the human in needof such treatment a therapeutically effective amount of crystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method fortreating or preventing an arthritis, asthma, fibrosis, lupus, allergy,fibromyalgia, wound healing, or inflammation resulting from surgicalcomplications in a human comprising topically administering to the humanin need of such treatment a therapeutically effective amount ofcrystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe form of a transdermal patch, an ointment, a lotion, a cream, or agel.

In another embodiment, the present invention provides a method fortreating or preventing inflammatory bowel disease, ulcerative colitis,or Crohn's disease in a human comprising administering to the human inneed of such treatment a therapeutically effective amount of crystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides the use ofcrystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe manufacture of a medicament for treating an inflammatory disease ina human.

In another embodiment, the present invention provides the use ofcrystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe manufacture of a medicament for treating atopic dermatitis, handdermatitis, contact dermatitis, allergic contact dermatitis, irritantcontact dermatitis, neurodermatitis, perioral dermatitis, stasisdermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis,seborrheic dermatitis, eyelid dermatitis, diaper dermatitis,dermatomyositis, lichen planus, lichen sclerosis, alopecia areata,vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasisalba, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria,chronic idiopathic urticaria, chronic physical urticaria,vogt-koyanagi-harada disease, sutton nevus/nevi, post inflammatoryhypopigmentation, senile leukoderma, chemical/drug-induced leukoderma,cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis,pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis,plaque psoriasis, pustular psoriasis, nail psoriasis, flexuralpsoriasis, guttate psoriasis, psoriatic arthritis, erythrodermicpsoriasis, or inverse psoriasis in a human.

In another embodiment, the present invention provides the use ofcrystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe manufacture of a medicament for treating arthritis, asthma,fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammationresulting from surgical complications in a human.

In another embodiment, the present invention provides the use ofcrystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe manufacture of a medicament for treating inflammatory bowel disease,ulcerative colitis, or Crohn's disease in a human.

In another embodiment, the present invention provides crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks18.7±0.2, 22.8±0.2, and 25.0±0.2 degrees two theta.

In another embodiment, the present invention provides crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks11.0±0.2, 11.4±0.2, 13.2 0.2, 18.7±0.2, 22.8±0.2, and 25.0±0.2, degreestwo theta.

In another embodiment, the present invention provides crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks11.0±0.2, 11.4±0.2, 13.2 0.2, 14.5±0.2, 15.1±0.2, 15.6±0.2, 18.7±0.2,22.8±0.2, and 25.0±0.2, degrees two theta.

In another embodiment, the present invention provides crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks11.0±0.2, 11.4±0.2, 13.2 0.2, 14.5±0.2, 15.1±0.2, 15.6±0.2, 18.7±0.2,19.7±0.2, 21.2±0.2, 22.8±0.2, 25.0±0.2, and 26.4±0.2 degrees two theta.

In another embodiment, the present invention provides crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks11.0±0.2, 11.4±0.2, 13.2 0.2, 14.5±0.2, 15.1±0.2, 15.6±0.2, 18.7±0.2,19.4±0.2, 19.7±0.2, 20.5±0.2, 21.2±0.2, 22.80.2, 25.00.2, 26.4±0.2,27.4±0.2, and 28.3±0.2, degrees two theta.

In another embodiment, the present invention provides crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising 3 to 10diffraction peaks listed in Table 9.

In another embodiment, the present invention provides crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising the diffractionpeaks listed in Table 9.

In another embodiment, the present invention provides crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern as depicted in FIG. 7.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-oland at least one pharmaceutically acceptable excipient, diluent, orcarrier.

In another embodiment, the present invention provides a method fortreating or preventing an inflammatory disease in a human comprisingadministering to the human in need of such treatment a therapeuticallyeffective amount of crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method fortreating or preventing atopic dermatitis, hand dermatitis, contactdermatitis, allergic contact dermatitis, irritant contact dermatitis,neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidroticeczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis,eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus,lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysisbullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis,acne, chronic spontaneous urticaria, chronic idiopathic urticaria,chronic physical urticaria, vogt-koyanagi-harada disease, suttonnevus/nevi, post inflammatory hypopigmentation, senile leukoderma,chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoidlupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome,hidradenitis suppurativa, psoriasis, plaque psoriasis, pustularpsoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis,psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in ahuman comprising administering to the human in need of such treatment atherapeutically effective amount of crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method fortreating or preventing atopic dermatitis, hand dermatitis, contactdermatitis, allergic contact dermatitis, irritant contact dermatitis,neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidroticeczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis,eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus,lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysisbullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis,acne, chronic spontaneous urticaria, chronic idiopathic urticaria,chronic physical urticaria, vogt-koyanagi-harada disease, suttonnevus/nevi, post inflammatory hypopigmentation, senile leukoderma,chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoidlupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome,hidradenitis suppurativa, psoriasis, plaque psoriasis, pustularpsoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis,psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in ahuman comprising topically administering to the human in need of suchtreatment a therapeutically effective amount of crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe form of a transdermal patch, an ointment, a lotion, a cream, or agel.

In another embodiment, the present invention provides a method fortreating or preventing an arthritis, asthma, fibrosis, lupus, allergy,fibromyalgia, wound healing, or inflammation resulting from surgicalcomplications in a human comprising administering to the human in needof such treatment a therapeutically effective amount of crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method fortreating or preventing an arthritis, asthma, fibrosis, lupus, allergy,fibromyalgia, wound healing, or inflammation resulting from surgicalcomplications in a human comprising topically administering to the humanin need of such treatment a therapeutically effective amount ofcrystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe form of a transdermal patch, an ointment, a lotion, a cream, or agel.

In another embodiment, the present invention provides a method fortreating or preventing inflammatory bowel disease, ulcerative colitis,or Crohn's disease in a human comprising administering to the human inneed of such treatment a therapeutically effective amount of crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides the use ofcrystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe manufacture of a medicament for treating an inflammatory disease ina human.

In another embodiment, the present invention provides the use ofcrystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe manufacture of a medicament for treating atopic dermatitis, handdermatitis, contact dermatitis, allergic contact dermatitis, irritantcontact dermatitis, neurodermatitis, perioral dermatitis, stasisdermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis,seborrheic dermatitis, eyelid dermatitis, diaper dermatitis,dermatomyositis, lichen planus, lichen sclerosis, alopecia areata,vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasisalba, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria,chronic idiopathic urticaria, chronic physical urticaria,vogt-koyanagi-harada disease, sutton nevus/nevi, post inflammatoryhypopigmentation, senile leukoderma, chemical/drug-induced leukoderma,cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis,pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis,plaque psoriasis, pustular psoriasis, nail psoriasis, flexuralpsoriasis, guttate psoriasis, psoriatic arthritis, erythrodermicpsoriasis, or inverse psoriasis in a human.

In another embodiment, the present invention provides the use ofcrystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe manufacture of a medicament for treating arthritis, asthma,fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammationresulting from surgical complications in a human.

In another embodiment, the present invention provides the use ofcrystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol inthe manufacture of a medicament for treating inflammatory bowel disease,ulcerative colitis, or Crohn's disease in a human.

In another embodiment, the present invention provides crystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides crystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks12.8±0.2, 20.4±0.2, and 25.7±0.2 degrees two theta.

In another embodiment, the present invention provides crystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks12.8±0.2, 17.9±0.2, 20.4±0.2, 22.9±0.2, 23.1±0.2, and 25.7±0.2 degreestwo theta.

In another embodiment, the present invention provides crystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks8.9±0.2, 12.0±0.2, 12.3±0.2, 12.8±0.2, 17.8±0.2, 20.4±0.2, 22.9±0.2,23.1±0.2, and 25.7±0.2 degrees two theta.

In another embodiment, the present invention provides crystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks8.9±0.2, 12.0±0.2, 12.3±0.2, 12.8±0.2, 13.9±0.2, 14.2±0.2, 17.60.2,17.8±0.2, 19.2±0.2, 19.4±0.2, 19.60.2, and 20.4±0.2 degrees two theta.

In another embodiment, the present invention provides crystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks8.9±0.2, 12.0±0.2, 12.3±0.2, 12.8±0.2, 13.9±0.2, 14.2±0.2, 17.60.2,17.80.2, 19.2±0.2, 19.4±0.2, 19.6±0.2, 20.4±0.2, 21.4±0.2, 22.0±0.2,22.3±0.2, 22.9±0.2, 23.1±0.2, and 25.7±0.2 degrees two theta.

In another embodiment, the present invention provides crystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising 3 to 10diffraction peaks listed in Table 10.

In another embodiment, the present invention provides crystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising the diffractionpeaks listed in Table 10.

In another embodiment, the present invention provides crystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern as depicted in FIG. 8.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising crystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-oland at least one pharmaceutically acceptable excipient, diluent, orcarrier.

In another embodiment, the present invention provides a method fortreating or preventing an inflammatory disease in a human comprisingadministering to the human in need of such treatment a therapeuticallyeffective amount of crystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method fortreating or preventing atopic dermatitis, hand dermatitis, contactdermatitis, allergic contact dermatitis, irritant contact dermatitis,neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidroticeczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis,eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus,lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysisbullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis,acne, chronic spontaneous urticaria, chronic idiopathic urticaria,chronic physical urticaria, vogt-koyanagi-harada disease, suttonnevus/nevi, post inflammatory hypopigmentation, senile leukoderma,chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoidlupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome,hidradenitis suppurativa, psoriasis, plaque psoriasis, pustularpsoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis,psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in ahuman comprising administering to the human in need of such treatment atherapeutically effective amount of crystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method fortreating or preventing atopic dermatitis, hand dermatitis, contactdermatitis, allergic contact dermatitis, irritant contact dermatitis,neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidroticeczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis,eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus,lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysisbullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis,acne, chronic spontaneous urticaria, chronic idiopathic urticaria,chronic physical urticaria, vogt-koyanagi-harada disease, suttonnevus/nevi, post inflammatory hypopigmentation, senile leukoderma,chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoidlupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome,hidradenitis suppurativa, psoriasis, plaque psoriasis, pustularpsoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis,psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in ahuman comprising topically administering to the human in need of suchtreatment a therapeutically effective amount of crystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olin the form of a transdermal patch, an ointment, a lotion, a cream, or agel.

In another embodiment, the present invention provides a method fortreating or preventing an arthritis, asthma, fibrosis, lupus, allergy,fibromyalgia, wound healing, or inflammation resulting from surgicalcomplications in a human comprising administering to the human in needof such treatment a therapeutically effective amount of crystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method fortreating or preventing an arthritis, asthma, fibrosis, lupus, allergy,fibromyalgia, wound healing, or inflammation resulting from surgicalcomplications in a human comprising topically administering to the humanin need of such treatment a therapeutically effective amount ofcrystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olin the form of a transdermal patch, an ointment, a lotion, a cream, or agel.

In another embodiment, the present invention provides a method fortreating or preventing inflammatory bowel disease, ulcerative colitis,or Crohn's disease in a human comprising administering to the human inneed of such treatment a therapeutically effective amount ofcrystalline(−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides the use ofcrystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olin the manufacture of a medicament for treating an inflammatory diseasein a human.

In another embodiment, the present invention provides the use ofcrystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olin the manufacture of a medicament for treating atopic dermatitis, handdermatitis, contact dermatitis, allergic contact dermatitis, irritantcontact dermatitis, neurodermatitis, perioral dermatitis, stasisdermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis,seborrheic dermatitis, eyelid dermatitis, diaper dermatitis,dermatomyositis, lichen planus, lichen sclerosis, alopecia areata,vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasisalba, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria,chronic idiopathic urticaria, chronic physical urticaria,vogt-koyanagi-harada disease, sutton nevus/nevi, post inflammatoryhypopigmentation, senile leukoderma, chemical/drug-induced leukoderma,cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis,pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis,plaque psoriasis, pustular psoriasis, nail psoriasis, flexuralpsoriasis, guttate psoriasis, psoriatic arthritis, erythrodermicpsoriasis, or inverse psoriasis in a human.

In another embodiment, the present invention provides the use ofcrystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olin the manufacture of a medicament for treating arthritis, asthma,fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammationresulting from surgical complications in a human.

In another embodiment, the present invention provides the use ofcrystalline (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olin the manufacture of a medicament for treating inflammatory boweldisease, ulcerative colitis, or Crohn's disease in a human.

In another embodiment, the present invention provides crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks21.1±0.2, 22.7±0.2, and 23.8±0.2 degrees two theta.

In another embodiment, the present invention provides crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks10.9±0.2, 11.3±0.2, 19.3±0.2, 21.1±0.2, 22.7±0.2, 23.8±0.2, and 30.4±0.2degrees two theta.

In another embodiment, the present invention provides crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks10.9±0.2, 11.3±0.2, 17.0±0.2, 17.3±0.2, 19.3±0.2, 21.1±0.2, 22.7±0.2,23.8±0.2, and 30.4±0.2 degrees two theta.

In another embodiment, the present invention provides crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising diffraction peaks10.9±0.2, 11.3±0.2, 17.0±0.2, 17.3±0.2, 19.0±0.2, 19.3±0.2, 21.1±0.2,22.7±0.2, 23.8±0.2, 25.4±0.2, 26.5±0.2, and 30.4±0.2 degrees two theta.

In another embodiment, the present invention provides crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising 3 to 10diffraction peaks listed in Table 11.

In another embodiment, the present invention provides crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern comprising the diffractionpeaks listed in Table 11.

In another embodiment, the present invention provides crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-olhaving an X-ray powder diffraction pattern as depicted in FIG. 9.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-oland at least one pharmaceutically acceptable excipient, diluent, orcarrier.

In another embodiment, the present invention provides a method fortreating or preventing an inflammatory disease in a human comprisingadministering to the human in need of such treatment a therapeuticallyeffective amount of crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method fortreating or preventing atopic dermatitis, hand dermatitis, contactdermatitis, allergic contact dermatitis, irritant contact dermatitis,neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidroticeczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis,eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus,lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysisbullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis,acne, chronic spontaneous urticaria, chronic idiopathic urticaria,chronic physical urticaria, vogt-koyanagi-harada disease, suttonnevus/nevi, post inflammatory hypopigmentation, senile leukoderma,chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoidlupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome,hidradenitis suppurativa, psoriasis, plaque psoriasis, pustularpsoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis,psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in ahuman comprising administering to the human in need of such treatment atherapeutically effective amount of crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method fortreating or preventing atopic dermatitis, hand dermatitis, contactdermatitis, allergic contact dermatitis, irritant contact dermatitis,neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidroticeczema, xerotic dermatitis, nummalar dermatitis, seborrheic dermatitis,eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus,lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysisbullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis,acne, chronic spontaneous urticaria, chronic idiopathic urticaria,chronic physical urticaria, vogt-koyanagi-harada disease, suttonnevus/nevi, post inflammatory hypopigmentation, senile leukoderma,chemical/drug-induced leukoderma, cutaneous lupus erythematosus, discoidlupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome,hidradenitis suppurativa, psoriasis, plaque psoriasis, pustularpsoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis,psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis in ahuman comprising topically administering to the human in need of suchtreatment a therapeutically effective amount of crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-olin the form of a transdermal patch, an ointment, a lotion, a cream, or agel.

In another embodiment, the present invention provides a method fortreating or preventing an arthritis, asthma, fibrosis, lupus, allergy,fibromyalgia, wound healing, or inflammation resulting from surgicalcomplications in a human comprising administering to the human in needof such treatment a therapeutically effective amount of crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides a method fortreating or preventing an arthritis, asthma, fibrosis, lupus, allergy,fibromyalgia, wound healing, or inflammation resulting from surgicalcomplications in a human comprising topically administering to the humanin need of such treatment a therapeutically effective amount ofcrystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-olin the form of a transdermal patch, an ointment, a lotion, a cream, or agel.

In another embodiment, the present invention provides a method fortreating or preventing inflammatory bowel disease, ulcerative colitis,or Crohn's disease in a human comprising administering to the human inneed of such treatment a therapeutically effective amount of crystalline(R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol.

In another embodiment, the present invention provides the use ofcrystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-olin the manufacture of a medicament for treating an inflammatory diseasein a human.

In another embodiment, the present invention provides the use ofcrystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-olin the manufacture of a medicament for treating atopic dermatitis, handdermatitis, contact dermatitis, allergic contact dermatitis, irritantcontact dermatitis, neurodermatitis, perioral dermatitis, stasisdermatitis, dyshidrotic eczema, xerotic dermatitis, nummalar dermatitis,seborrheic dermatitis, eyelid dermatitis, diaper dermatitis,dermatomyositis, lichen planus, lichen sclerosis, alopecia areata,vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasisalba, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria,chronic idiopathic urticaria, chronic physical urticaria,vogt-koyanagi-harada disease, sutton nevus/nevi, post inflammatoryhypopigmentation, senile leukoderma, chemical/drug-induced leukoderma,cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis,pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis,plaque psoriasis, pustular psoriasis, nail psoriasis, flexuralpsoriasis, guttate psoriasis, psoriatic arthritis, erythrodermicpsoriasis, or inverse psoriasis in a human.

In another embodiment, the present invention provides the use ofcrystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-olin the manufacture of a medicament for treating arthritis, asthma,fibrosis, lupus, allergy, fibromyalgia, wound healing, or inflammationresulting from surgical complications in a human.

In another embodiment, the present invention provides the use ofcrystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-olin the manufacture of a medicament for treating inflammatory boweldisease, ulcerative colitis, or Crohn's disease in a human.

In another embodiment, the present invention provides pharmaceuticalcombinations for topical administration comprising a compound of Formula(I), Formula (IA), Formula (IB), or Formula (IC), or a pharmaceuticallyacceptable salt thereof, in combination with another pharmaceuticalagent for the treatment of the diseases, conditions and/or disordersdescribed herein. Suitable pharmaceutical agents that may be used incombination with the compounds of the present invention for topicaladministration include, but are not limited to: a second compound ofFormula (I), Formula (IA), Formula (IB), or Formula (IC); a PDE4isoenzyme inhibitor including, but not limited to, crisaborole,ampremilast, roflumilast, rolipram and piclamilast; a corticosteroidincluding, but not limited to, fluocinonide, desoximetasone, mometasone,triamcinolone, betamethasone, alclometasone, desonide, hydrocortisoneand mapracorat; a calcineurin inhibitor including, but not limited to,tacrolimus, pimecrolimus and cyclosporine; a JAK inhibitor including,but not limited to, tofacitinib, ATI-502, SNA-152, SHR-0302, JTE052,BMS-986165, filgotinib, baricitinib, upadacitinib, ruxolitinib,peficitinib, PF-04965842, PF-06651600, PF-06700841, and PF06826647; anaryl hydrocarbon receptor agonist including, but not limited to,tapinarof; an IRAK4 inhibitor including, but not limited to,PF-06650833; a non-steroidal anti-inflammatory including, but notlimited to, WBI-1001 and MRX-6; vitamin D analog such as calcipotriene;retinoic acid derivatives including, but not limited to, alitretinoin; aliver X receptor (LXR) selective agonist including, but not limited to,VTP-38543; a H4 receptor antagonists including, but not limited to,ZPL-389; a NKI receptor antagonists including, but not limited to,Aprepitant and Tradipitant; a CRTH2 receptor antagonists including, butnot limited to, Fevipiprant and OC-459; a Chymase inhibitors including,but not limited to, SUN 13834; a GATA-3 inhibitors including, but notlimited to, SB-011 and GR-MD-02; and a ROR inverse agonists including,but not limited to, VTP-43742, ARN6039, TAK-828 and JTE-451;immunomodulators such as PF-06763809, and inhibitors of SYK, BTK, andITK, including but not limited to, R-348, cerdulatinib, ibrutinib,entospletinib, tirabrutinib, and JTE-051.

In another embodiment, the present invention provides pharmaceuticalcombinations for oral administration comprising a compound of Formula(I), Formula (IA), Formula (IB), or Formula (IC), or a pharmaceuticallyacceptable salt thereof, in combination with another pharmaceuticalagent for the treatment of the diseases, conditions and/or disordersdescribed herein. Suitable pharmaceutical agents that may be used incombination with the compounds of the present invention for oraladministration include, but are not limited to: oral retinoic acidderivatives including, but not limited to, alitretinoin; oral liver Xreceptor (LXR) selective agonists including, but not limited to,VTP-38543; oral H4 receptor antagonists including, but not limited to,ZPL-389; oral NKI receptor antagonists including, but not limited to,Aprepitant and Tradipitant; oral CRTH2 receptor antagonists including,but not limited to, Fevipiprant and OC-459; oral Chymase inhibitorsincluding, but not limited to, SUN 13834; oral GATA-3 inhibitorsincluding, but not limited to, SB-011; oral ROR inverse agonistsincluding, but not limited to, VTP-43742, ARN6039, TAK-828 and JTE-451;oral JAK inhibitors including, but not limited to, baricitinib,cerdulatinib, decernotinib, delgocitinib, fedratinib, filgotinib,gandotinib, ilginatinib, itacitinib, lestaurtinib, momelotinib,oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib,upadacitinib, ASN-002, AT9283, ATI-501, ATI-502, AZD1480, AZD4205,BMS-911543, BMS-986165, INCB-52793, INCB-54707, PF-04965842,PF-06263276, PF-06651600, PF-06700841, PF-06826647, SHR-0302, SNA-125,or TD-1473; immunomodulators and inhibitors of SYK, BTK, and ITK,including but not limited to, fostamatinib, ibrutinib, mastinib,mivavotinib, entospletinib, sperbrutinib, tirabrutinib, fenebrutinib,TOP-1288, R-348, cerdulatinib, SKI-O-703, TAS-05567, CG-806, R-343,CG-103065, PRT-2607, GSK-143, VRT-750018, UR-67767, PRN-1008,BMS-935177, PRN-473, ABBV-105, AS-550, M-7583, WXFL-10230486, LOU-064,AEG-42766, HCI-1401, KBP-7536, ARQ-531, GNE-4997, and GNE-9822; and oralIRAK4 inhibitors including, but not limited to, PF-06650833 andBAY-1830839.

In another embodiment, the present invention provides pharmaceuticalcombinations for injectable administration comprising a compound ofFormula (I), Formula (IA), Formula (IB), or Formula (IC), or apharmaceutically acceptable salt thereof, in combination with anotherpharmaceutical agent for the treatment of the diseases, conditionsand/or disorders described herein. Suitable pharmaceutical agents thatmay be used in combination with the compounds of the present inventionfor injectable administration include, but are not limited to: TNFαinhibitors including, but not limited to, infliximab, adalimumab,golimumab, certolizumab pegol; injectable anti-IL4, IL-12, IL-17, IL-22,IL-23, IL-31, IL-33, IgE treatments such as dupilumab, lebrikizumab,nemolizumab, tralokinumab, etanercept, adalimumab, infliximab,ustekinumab, secukinumab, OmaZumilab, and CIM-331.

Combination therapy includes administration of the two or moretherapeutic agents concurrently or sequentially. The agents may beadministered in any order. Alternatively, the multiple therapeuticagents can be combined into a single composition that can beadministered to the patient. For instance, a single pharmaceuticalcomposition could comprise the compound or pharmaceutically acceptablesalt, ester or prodrug thereof according to the Formulae (I), (IA),(IB), and (IC), another therapeutic agent or a pharmaceuticallyacceptable salt, ester or prodrug thereof, and at least onepharmaceutically acceptable excipient or carrier.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention can be employedin pure form or, where such forms exist, in pharmaceutically acceptablesalt, ester, amide, or prodrug form. Alternatively, the compound can beadministered as a pharmaceutical composition containing the compound ofinterest in combination with one or more pharmaceutically acceptablecarriers. The phrase “therapeutically effective amount” of the compoundof the present invention means a sufficient amount of the compound totreat the diseases, conditions, or disorders indicated herein at areasonable benefit/risk ratio applicable to any medical treatment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts.

Pharmaceutical Compositions or Formulations

In another embodiment, the present invention provides pharmaceuticalcompositions, or formulations, comprising a therapeutically effectiveamount of a compound of the present invention and a pharmaceuticallyacceptable excipient, diluent or carrier. The pharmaceuticalcompositions, or formulations, of this invention may be administered tohumans and other mammals topically, orally, parenterally,intracisternally, intravaginally, intraperitoneally, bucally, as an oralspray, as a nasal spray, rectally as a suppository, or in the form of aliposome.

A typical pharmaceutical composition or formulation is prepared bymixing a compound of the present invention and a carrier, diluent orexcipient. Suitable carriers, diluents and excipients include materialssuch as carbohydrates, waxes, water soluble and/or swellable polymers,hydrophilic or hydrophobic materials, gelatin, oils, solvents, water,and the like. The particular carrier, diluent or excipient used willdepend upon the means and purpose for which the compound of the presentinvention is being applied. Suitable aqueous solvents include water,ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300),etc. and mixtures thereof. The formulations may also include one or morebuffers, stabilizing agents, surfactants, wetting agents, lubricatingagents, emulsifiers, suspending agents, preservatives, antioxidants,opaquing agents, glidants, processing aids, colorants, sweeteners,perfuming agents, flavoring agents and other known additives to providean elegant presentation of the drug (i.e., a compound of the presentinvention or pharmaceutical composition thereof) or aid in themanufacturing of the pharmaceutical product (i.e., for use in thepreparing a medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof the present invention or stabilized form of the compound (e.g.,complex with a cyclodextrin derivative or other known complexationagent)) is dissolved in a suitable solvent in the presence of one ormore of the excipients described above. The dissolution rate of poorlywater-soluble compounds may be enhanced by the use of a spray-drieddispersion, such as those described by Takeuchi, H., et al. in“Enhancement of the dissolution rate of a poorly water-soluble drug(tolbutamide) by a spray-drying solvent deposition method anddisintegrants” J. Pharm. Pharmacol., 39, 769-773 (1987); and EP0901786B1 (US2002/009494), incorporated herein by reference. The compound ofthe present invention is typically formulated into pharmaceutical dosageforms to provide an easily controllable dosage of the drug and to givethe patient an elegant and easily handleable product.

The pharmaceutical composition, or formulation, for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers include materials such asbottles (plastic and glass), sachets, ampoules, plastic bags, metalcylinders, and the like. The container may also include a tamper-proofassemblage to prevent indiscreet access to the contents of the package.In addition, the container has deposited thereon a label that describesthe contents of the container. The label may also include appropriatewarnings.

The term “pharmaceutically acceptable carrier” refers to carrier mediumthat provides the appropriate delivery of an effective amount of aactive agent as defined herein, does not interfere with theeffectiveness of the biological activity of the active agent, and thatis sufficiently non-toxic to the host or patient. Representativecarriers include water, oils, both vegetable and mineral, cream bases,lotion bases, ointment bases and the like. These bases includesuspending agents, thickeners, penetration enhancers, and the like.Additional information concerning carriers can be found in Remington:The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams &Wilkins (2005) which is incorporated herein by reference. Furtherexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as cocoabutter and suppository waxes; oils such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols;such a propylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

The term “pharmaceutically acceptable topical carrier” refers topharmaceutically acceptable carriers, as described herein above,suitable for topical application. An inactive liquid or cream vehiclecapable of suspending or dissolving the active agent(s), and having theproperties of being nontoxic and non-inflammatory when applied to theskin, nail, hair, claw or hoof is an example of apharmaceutically-acceptable topical carrier. This term is specificallyintended to encompass carrier materials approved for use in topicalcosmetics as well.

The term “topical administration” refers to the application of apharmaceutical agent to the external surface of the skin, nail, hair,claw or hoof, such that the agent crosses the external surface of theskin, nail, hair, claw or hoof and enters the underlying tissues.Topical administration includes application of the composition to intactskin, nail, hair, claw or hoof, or to a broken, raw or open wound ofskin, nail, hair, claw or hoof. Topical administration of apharmaceutical agent can result in a limited distribution of the agentto the skin and surrounding tissues or, when the agent is removed fromthe treatment area by the bloodstream, can result in systemicdistribution of the agent.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Compounds that are volatile in may require admixture with specialformulating agents or with special packaging materials to assure properdosage delivery. In addition, compounds of the present invention thathave poor human skin permeability may require one or more permeabilityenhancers whereas compounds rapidly absorbed through the skin mayrequire formulation with absorption-retarding agents or barriers.

The ointments, pastes, creams, lotions, gels, powders, and solutions,for topical administration may contain, in addition to an activecompound of the present invention, pharmaceutically acceptableexcipients such as animal and vegetable fats, oils, waxes, paraffins,starch, tragacanth, cellulose derivatives, polyethylene glycols,silicones, bentonites, silicic acid, talc, zinc oxide, preservatives,antioxidants, fragrances, emulsifiers, dyes, inert fillers,anti-irritants, tackifiers, fragrances, opacifiers, antioxidants,gelling agents, stabilizers, surfactants, emollients, coloring agents,preservatives, buffering agents, permeation enhancers, or mixturesthereof. Topical excipients should not interfere with the effectivenessof the biological activity of the active agent and not be deleterious tothe epithelial cells or their function.

The terms “permeability enhancer,” or “permeation enhancer,” relates toan increase in the permeability of the skin, nail, hair, claw or hoof toa drug, so as to increase the rate at which the drug permeates throughthe skin, nail, hair, claw or hoof. The enhanced permeation effectedthrough the use of such enhancers can be observed, for example, bymeasuring the rate of diffusion of the drug through animal or humanskin, nail, hair, claw or hoof using a diffusion cell apparatus. Adiffusion cell is described by Merritt et al. Diffusion Apparatus forSkin Penetration, J of Controlled Release, 1 (1984) pp. 161-162. Theterm “permeation enhancer” or “penetration enhancer” intends an agent ora mixture of agents, which, alone or in combination, act to increase thepermeability of the skin, nail, hair or hoof to a drug.

The term “transdermal delivery” refers to the diffusion of an agentacross the barrier of the skin, nail, hair, claw or hoof resulting fromtopical administration or other application of a composition. Thestratum corneum acts as a barrier and few pharmaceutical agents are ableto penetrate intact skin. In contrast, the epidermis and dermis arepermeable to many solutes and absorption of drugs therefore occurs morereadily through skin, nail, hair, claw or hoof that is abraded orotherwise stripped of the stratum corneum to expose the epidermis.Transdermal delivery includes injection or other delivery through anyportion of the skin, nail, hair, claw or hoof or mucous membrane andabsorption or permeation through the remaining portion. Absorptionthrough intact skin, nail, hair, claw or hoof can be enhanced by placingthe active agent in an appropriate pharmaceutically acceptable vehiclebefore application to the skin, nail, hair, claw or hoof. Passivetopical administration may consist of applying the active agent directlyto the treatment site in combination with emollients or penetrationenhancers. As used herein, transdermal delivery is intended to includedelivery by permeation through or past the integument, i.e. skin, nail,hair, claw or hoof.

Powders and sprays can contain, in addition to the compounds of thisinvention, lactose, talc, silicic acid, aluminum hydroxide, calciumsilicates and polyamide powder, or mixtures of these substances. Sprayscan additionally contain customary propellants such aschlorofluorohydrocarbons.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert pharmaceutically acceptablecarrier such as sodium citrate or calcium phosphate and/or a) fillers orextenders such as starches, lactose, sucrose, glucose, mannitol, andsalicylic acid; b) binders such as carboxymethylcellulose, alginates,gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants suchas glycerol; d) disintegrating agents such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; e) solution retarding agents such as paraffin; f)absorption accelerators such as quaternary ammonium compounds; g)wetting agents such as cetyl alcohol and glycerol monostearate; h)absorbents such as kaolin and bentonite clay; and i) lubricants such astalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof. In the case of capsules,tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using lactose or milk sugar aswell as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract in a delayedmanner. Examples of embedding compositions which can be used includepolymeric substances and waxes.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

The term “parenterally,” as used herein, refers to modes ofadministration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous, intraarticular injectionand infusion. Pharmaceutical compositions of this invention forparenteral injection comprise pharmaceutically acceptable sterileaqueous or nonaqueous solutions, dispersions, suspensions or emulsionsand sterile powders for reconstitution into sterile injectable solutionsor dispersions. Examples of suitable aqueous and nonaqueous carriers,diluents, solvents or vehicles include water, ethanol, polyols(propylene glycol, polyethylene glycol, glycerol, and the like),suitable mixtures thereof, vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate. Proper fluidity may bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case ofdispersions, and by the use of surfactants.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides) Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution, suspension or emulsion in anontoxic, parenterally acceptable diluent or solvent such as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution, U.S.P. and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose any blandfixed oil can be employed including synthetic mono- or diglycerides. Inaddition, fatty acids such as oleic acid are used in the preparation ofinjectables.

Pharmaceutical compositions, or formulations, for rectal or vaginaladministration are preferably suppositories which can be prepared bymixing the compounds of this invention with suitable non-irritatingcarriers such as cocoa butter, polyethylene glycol or a suppository waxwhich are solid at ambient temperature but liquid at body temperatureand therefore melt in the rectum or vaginal cavity and release theactive compound.

Compounds of the present invention may also be administered in the formof liposomes. Liposomes are generally derived from phospholipids orother lipid substances and are formed by mono- or multi-lamellarhydrated liquid crystals that are dispersed in an aqueous medium. Anynon-toxic, physiologically acceptable and metabolizable lipid capable offorming liposomes may be used. The present compositions in liposome formmay contain, in addition to the compounds of the present invention,stabilizers, preservatives, and the like. The preferred lipids are thenatural and synthetic phospholipids and phosphatidylcholines (lecithins)used separately or together. Methods to form liposomes are known in theart. See, for example, Prescott, Ed., Methods in Cell Biology, VolumeXIV, Academic Press, New York, N. Y., (1976), p 33 et seq.

Pharmaceutical compositions, or formulations, of the present inventionmay also contain adjuvants such as preservative agents, wetting agents,emulsifying agents, and dispersing agents. Prevention of the action ofmicroorganisms may be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample, sugars, sodium chloride and the like. Prolonged absorption ofthe injectable pharmaceutical form may be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

The pharmaceutical compositions, or formulations, of the invention maybe suspensions. Suspensions, in addition to the active compounds, maycontain suspending agents, as, for example, ethoxylated isostearylalcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, andmixtures thereof.

The pharmaceutical compositions also include solvates and hydrates ofthe compounds of the present invention. The term “solvate” refers to amolecular complex of a compound represented by Formulae (I), (IA), (IB),and (IC), including pharmaceutically acceptable salts thereof, with oneor more solvent molecules. Such solvent molecules are those commonlyused in the pharmaceutical art, which are known to be innocuous to therecipient, e.g., water, ethanol, ethylene glycol, (S)-propylene glycol,(R)-propylene glycol, and the like, The term “hydrate” refers to thecomplex where the solvent molecule is water. The solvates and/orhydrates preferably exist in crystalline form. Other solvents may beused as intermediate solvates in the preparation of more desirablesolvates. Intermediate solvents include, but are not limited to,methanol, methyl t-butyl ether, ethyl acetate, methyl acetate,1,4-butyne-diol, and the like.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions, and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated, and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required for toachieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa human or lower animal may range from about 0.000001 to about 10mg/kg/day. For purposes of oral administration, more preferable dosescan be in the range of from about 0.001 to about 1 mg/kg/day. Fortopical administration, more preferable doses can be in the range of0.00001 mg/kg/day to about 5 mg/kg/day. If desired, the effective dailydose can be divided into multiple doses for purposes of administration,e.g. two to four separate doses per day.

Definitions

As used throughout this specification and the appended claims, thefollowing terms have the following meanings:

The term “(C₂-C₆)alkenyl” as used herein, means a straight or branchedchain hydrocarbon containing from 2 to 6 carbons and containing at leastone carbon-carbon double bond. Representative examples of (C₂-C₆)alkenylinclude, but are not limited to, ethenyl, 2-propenyl,2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.

The term “(C₂-C₆)alkenyloxy” as used herein, means a (C₂-C₆)alkenylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom.

The term “(C₂-C₆)alkenylthio” as used herein, means a (C₂-C₆)alkenylgroup, as defined herein, appended to the parent molecular moietythrough a sulfur atom.

The term “(C₁-C₆)alkoxy” as used herein, means a (C₁-C₆)alkyl group, asdefined herein, appended to the parent molecular moiety through anoxygen atom. Representative examples of (C₁-C₆)alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, and hexyloxy.

The term “(C₁-C₆)alkoxy-d₁-13” as used herein, means a(C₁-C₆)alkyl-d₁₋₁₃, group, as defined herein, appended to the parentmolecular moiety through an oxygen atom.

Representative examples of (C₁-C₆)alkoxy-d₁₋₁₃ include, but are notlimited to, methoxy-d₃, ethoxy-ds, propoxy-d₇, 2-propoxy-d₇, butoxy-ds,tert-butoxy-ds, pentyloxy-d₁₁, and hexyloxy-d₁₃.

The term “(C₁-C₆)alkoxy(C₁-C₆)alkoxy” as used herein, means a(C₁-C₆)alkoxy group, as defined herein, appended to the parent molecularmoiety through another (C₁-C₆)alkoxy group, as defined herein.Representative examples of (C₁-C₆)alkoxy(C₁-C₆)alkoxy include, but arenot limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, andmethoxymethoxy.

The term “(C₁-C₆)alkoxy(C₁-C₆)alkyl” as used herein, means a(C₁-C₆)alkoxy group, as defined herein, appended to the parent molecularmoiety through a (C₁-C₆)alkyl group, as defined herein. Representativeexamples of (C₁-C₆)alkoxy(C₁-C₆)alkyl include, but are not limited to,tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.

The term “(C₁-C₆)alkoxycarbonyl” as used herein, means a (C₁-C₆)alkoxygroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(C₁-C₆)alkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “(C₁-C₃)alkyl” as used herein, means a straight or branchedchain hydrocarbon containing from 1 to 3 carbon atoms. Representativeexamples of (C₁-C₃)alkyl include methyl, ethyl, n-propyl, andiso-propyl.

The term “(C₁-C₃)alkyl-d₁₋₇” as used herein, means a straight orbranched chain hydrocarbon containing from 1 to 3 carbon atoms whereinone to seven of the hydrogens have been exchanged for deuterium (²H orD). Representative examples of (C₁-C₃)alkyl-d₁₋₇ include methyl-d₃,ethyl-ds, ethyl-2,2,2-d₃, propyl-d₇, and 2-propyl-d₇.

The term “(C₁-C₆)alkyl” as used herein, means a straight or branchedchain hydrocarbon containing from 1 to 6 carbon atoms. Representativeexamples of (C₁-C₆)alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, and n-hexyl.

The term “(C₁-C₆)alkyl-d₁-13” as used herein, means a straight orbranched chain hydrocarbon containing from 1 to 6 carbon atoms whereinone to thirteen of the hydrogens have been exchanged for deuterium (²Hor D). Representative examples of (C₁-C₆)alkyl-d₁₋₁₃ include, but arenot limited to, methyl-d₃, ethyl-ds, ethyl-2,2,2-d₃, propyl-d₇,2-propyl-d₇, butyl-d, tert-butyl-d, pentyl-d₁₁, and hexyl-d₁₃.

The term “(C₁-C₆)alkylcarbonyl” as used herein, means a (C₁-C₆)alkylgroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(C₁-C₆)alkylcarbonyl include, but are not limited to, acetyl,1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “(C₁-C₆)alkylthio” as used herein, means a (C₁-C₆)alkyl group,as defined herein, appended to the parent molecular moiety through asulfur atom. Representative examples of (C₁-C₆)alkylthio include, butare not limited to, methylthio, ethylthio, tert-butylthio, andhexylthio.

The term “(C₁-C₆)alkylthio(C₁-C₆)alkyl” as used herein, means a(C₁-C₆)alkylthio group, as defined herein, appended to the parentmolecular moiety through a (C₁-C₆)alkyl group, as defined herein.Representative examples of (C₁-C₆)alkylthio(C₁-C₆)alkyl include, but arenot limited to, methylthiomethyl and 2-(ethylthio)ethyl.

The term “(C₂-C₆)alkynyl” as used herein, means a straight or branchedchain hydrocarbon group containing from 2 to 6 carbon atoms andcontaining at least one carbon-carbon triple bond. Representativeexamples of (C₂-C₆)alkynyl include, but are not limited to, toacetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and1-butynyl.

The term “(C₂-C₆)alkynyloxy” as used herein, means a (C₂-C₆)alkynylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom.

The term “(C₂-C₆)alkynylthio” as used herein, means a (C₂-C₆)alkynylgroup, as defined herein, appended to the parent molecular moietythrough a sulfur atom.

The term “aryl,” as used herein, means a phenyl or naphthyl group.

The term “aryl(C₁-C₆)alkoxy” as used herein, means an aryl group, asdefined herein, appended to the parent molecular moiety through an(C₁-C₆)alkoxy group, as defined herein.

The term “aryl(C₁-C₆)alkyl” as used herein, means an aryl group, asdefined herein, appended to the parent molecular moiety through an(C₁-C₆)alkyl group, as defined herein.

Representative examples of aryl(C₁-C₆)alkyl include, but are not limitedto, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.

The term “aryl(C₁-C₆)alkylthio” as used herein, means anaryl(C₁-C₆)alkyl group, as defined herein, appended to the parentmolecular moiety through sulfur atom, as defined herein.

Representative examples of aryl(C₁-C₆)alkylthio include, but are notlimited to, benzylthio, phenylethylthio, 3-phenylpropylthio, and2-naphth-2-ylethylthio.

The term “aryloxy” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of aryloxy include, but are not limited to,phenoxy and naphthalenyloxy.

The term “arylthio” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of arylthio include, but are not limited to,phenylthio and naphthalenylthio.

The term “carbonyl” as used herein, means a —C(O)— group.

The term “carboxy” as used herein, means a —C(O)OH group.

The term “carboxy(C₁-C₆)alkoxy” as used herein, means a carboxy group,as defined herein, is attached to the parent molecular moiety through a(C₁-C₆)alkoxy group, as defined herein.

The term “carboxy(C₁-C₆)alkyl” as used herein, means a carboxy group, asdefined herein, is attached to the parent molecular moiety through a(C₁-C₆)alkyl group, as defined herein.

The term “cyano” as used herein, means a —CN group.

The term “(C₃-C₈)cycloalkyl” as used herein, means a saturated cyclichydrocarbon group containing from 3 to 8 carbons, examples of(C₃-C₈)cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl.

The term “(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy” as used herein, means a(C₃-C₈)cycloalkyl group, as defined herein, appended to the parentmolecular moiety through a (C₁-C₆)alkoxy group, as defined herein.

The term “(C₃-C₈)cycloalkyl(C₁-C₆)alkyl” as used herein, means a(C₃-C₆)cycloalkyl group, as defined herein, appended to the parentmolecular moiety through a (C₁-C₆)alkyl group, as defined herein.Representative examples of (C₃-C₈)cycloalkyl(C₁-C₆)alkyl include, butare not limited to, cyclopropylmethyl, 2-cyclobutylethyl,cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.

The term “(C₃-C₈)cycloalkyl(C₁-C₆)alkylthio” as used herein, means a(C₃-C₈)cycloalkyl(C₁-C₆)alkyl group, as defined herein, appended to theparent molecular moiety through a sulfur atom.

The term “(C₃-C₈)cycloalkyloxy” as used herein, means (C₃-C₈)cycloalkylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom, as defined herein. Representative examples of(C₃-C₈)cycloalkyloxy include, but are not limited to, cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, andcyclooctyloxy.

The term “(C₃-C₈)cycloalkylthio” as used herein, means (C₃-C₈)cycloalkylgroup, as defined herein, appended to the parent molecular moietythrough a sulfur atom, as defined herein. Representative examples of(C₃-C₈)cycloalkylthio include, but are not limited to, cyclopropylthio,cyclobutylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio, andcyclooctylthio.

The term “formyl” as used herein, means a —C(O)H group.

The term “halo” or “halogen” as used herein, means —C, —Br, —I or —F.

The term “halo(C₁-C₆)alkoxy” as used herein, means at least one halogen,as defined herein, appended to the parent molecular moiety through a(C₁-C₆)alkoxy group, as defined herein. Representative examples ofhalo(C₁-C₆)alkoxy include, but are not limited to, chloromethoxy,2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.

The term “halo(C₁-C₆)alkyl” as used herein, means at least one halogen,as defined herein, appended to the parent molecular moiety through a(C₁-C₆)alkyl group, as defined herein. Representative examples ofhalo(C₁-C₆)alkyl include, but are not limited to, chloromethyl,2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and2-chloro-3-fluoropentyl.

The term “halo(C₁-C₆)alkylthio” as used herein, means a halo(C₁-C₆)alkylgroup, as defined herein, appended to the parent molecular moietythrough a sulfur atom. Representative examples of halo(C₁-C₆)alkylthioinclude, but are not limited to, trifluoromethylthio.

The term “(5-6 membered)heteroaryl,” as used herein, means a 5 or 6membered monocyclic heteroaryl. The 5 membered ring consists of twodouble bonds and one, two, three or four nitrogen atoms and/oroptionally one oxygen or sulfur atom. The 6 membered ring consists ofthree double bonds and one, two, three or four nitrogen atoms. The 5 or6 membered heteroaryl is connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within theheteroaryl. Representative examples of monocyclic heteroaryl include,but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, and triazinyl.

The term “(5-6 membered)heteroaryl(C₁-C₆)alkoxy” as used herein, means a(5-6 membered)heteroaryl, as defined herein, appended to the parentmolecular moiety through an (C₁-C₆)alkoxy group, as defined herein.Representative examples of heteroaryl(C₁-C₆)alkoxy include, but are notlimited to, fur-3-ylmethoxy, 1H-imidazol-2-ylmethoxy,1H-imidazol-4-ylmethoxy, 1-(pyridin-4-yl)ethoxy, pyridin-3-ylmethoxy,6-chloropyridin-3-ylmethoxy, pyridin-4-ylmethoxy,(6-(trifluoromethyl)pyridin-3-yl)methoxy,(6-(cyano)pyridin-3-yl)methoxy, (2-(cyano)pyridin-4-yl)methoxy,(5-(cyano)pyridin-2-yl)methoxy, (2-(chloro)pyridin-4-yl)methoxy,pyrimidin-5-ylmethoxy, 2-(pyrimidin-2-yl)propoxy, thien-2-ylmethoxy, andthien-3-ylmethoxy.

The term “(5-6 membered)heteroaryl(C₁-C₆)alkyl” as used herein, means a(5-6 membered)heteroaryl, as defined herein, appended to the parentmolecular moiety through an (C₁-C₆)alkyl group, as defined herein.Representative examples of heteroaryl(C₁-C₆)alkyl include, but are notlimited to, fur-3-ylmethyl, 1H-imidazol-2-ylmethyl,1H-imidazol-4-ylmethyl, 1-(pyridin-4-yl)ethyl, pyridin-3-ylmethyl,6-chloropyridin-3-ylmethyl, pyridin-4-ylmethyl,(6-(trifluoromethyl)pyridin-3-yl)methyl, (6-(cyano)pyridin-3-yl)methyl,(2-(cyano)pyridin-4-yl)methyl, (5-(cyano)pyridin-2-yl)methyl,(2-(chloro)pyridin-4-yl)methyl, pyrimidin-5-ylmethyl,2-(pyrimidin-2-yl)propyl, thien-2-ylmethyl, and thien-3-ylmethyl.

The term “(5-6 membered)heteroaryl(C₁-C₆)alkylthio” as used herein,means a (5-6 membered)heteroaryl(C₁-C₆)alkyl group, as defined herein,appended to the parent molecular moiety through a sulfur atom.Representative examples of heteroaryl(C₁-C₆)alkylthio include, but arenot limited to, fur-3-ylmethylthio, 1H-imidazol-2-ylmethylthio,1H-imidazol-4-ylmethylthio, pyridin-3-ylmethylthio,6-chloropyridin-3-ylmethylthio, pyridin-4-ylmethylthio,(6-(trifluoromethyl)pyridin-3-yl)methylthio,(6-(cyano)pyridin-3-yl)methylthio, (2-(cyano)pyridin-4-yl)methylthio,(5-(cyano)pyridin-2-yl)methylthio, (2-(chloro)pyridin-4-yl)methylthio,pyrimidin-5-ylmethylthio, 2-(pyrimidin-2-yl)propylthio,thien-2-ylmethylthio, and thien-3-ylmethylthio.

The term “(5-6 membered)heteroaryloxy” as used herein, means a (5-6membered)heteroaryl, as defined herein, appended to the parent molecularmoiety through an oxygen atom. Representative examples of heteroaryloxyinclude, but are not limited to, fur-3-yloxy, 1H-imidazol-2-yloxy,1H-imidazol-4-yloxy, pyridin-3-yloxy, 6-chloropyridin-3-yloxy,pyridin-4-yloxy, (6-(trifluoromethyl)pyridin-3-yl) oxy,(6-(cyano)pyridin-3-yl) oxy, (2-(cyano)pyridin-4-yl)oxy,(5-(cyano)pyridin-2-yl)oxy, (2-(chloro)pyridin-4-yl)oxy,pyrimidin-5-yloxy, pyrimidin-2-yloxy, thien-2-yloxy, and thien-3-yloxy.

The term “(5-6 membered)heteroarylthio” as used herein, means a (5-6membered)heteroaryl, as defined herein, appended to the parent molecularmoiety through a sulfur atom. Representative examples of heteroarylthioinclude, but are not limited to, pyridin-3-ylthio and quinolin-3-ylthio.

The term “(4-7 membered)heterocycle” or “heterocyclic” as used herein,means a 4, 5, 6 or 7 membered ring containing at least one heteroatomindependently selected from the group consisting of O, N, and S. The 4membered ring contains 1 heteroatom selected from the group consistingof O, N and S. The 5 membered ring contains zero or one double bond andone, two or three heteroatoms selected from the group consisting of O, Nand S. The 6 or 7 membered ring contains zero, one or two double bondsand one, two or three heteroatoms selected from the group consisting ofO, N and S. The heterocycle is connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within theheterocycle. Representative examples of heterocycle include, but are notlimited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl,1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl,imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl,oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl,pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl,thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl.

The term “(4-7 membered)heterocycle(C₁-C₆)alkoxy” as used herein, meansa (4-7 membered)heterocycle, as defined herein, appended to the parentmolecular moiety through an (C₁-C₆)alkoxy group, as defined herein.

The term “(4-7 membered)heterocycle(C₁-C₆)alkyl” as used herein, means a(4-7 membered)heterocycle, as defined herein, appended to the parentmolecular moiety through an (C₁-C₆)alkyl group, as defined herein.

The term “(4-7 membered)heterocycle(C₁-C₆)alkylthio” as used herein,means a (4-7 membered)heterocycle(C₁-C₆)alkyl group, as defined herein,appended to the parent molecular moiety through a sulfur atom.

The term “(4-7 membered)heterocycleoxy” as used herein, means a (4-7membered)heterocycle, as defined herein, appended to the parentmolecular moiety through an oxygen atom. Representative examples ofheteroaryloxy include, but are not limited to, pyridin-3-yloxy andpyrimidin-2-yloxy.

The term “(4-7 membered)heterocyclethio” as used herein, means a (4-7membered)heterocycle, as defined herein, appended to the parentmolecular moiety through a sulfur atom. Representative examples ofheteroarylthio include, but are not limited to, pyridin-3-ylthio andpyrimidin-2-ylthio.

The term “hydroxy” as used herein, means an —OH group.

The term “hydroxy(C₁-C₆)alkoxy” as used herein, means at least onehydroxy group, as defined herein, is appended to the parent molecularmoiety through a (C₁-C₆)alkoxy group, as defined herein. Representativeexamples of hydroxy(C₁-C₆)alkoxy include, but are not limited to,hydroxymethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypentoxy,and 2-ethyl-4-hydroxyheptoxy.

The term “hydroxy(C₁-C₆)alkyl” as used herein, means at least onehydroxy group, as defined herein, is appended to the parent molecularmoiety through a (C₁-C₆)alkyl group, as defined herein. Representativeexamples of hydroxy(C₁-C₆)alkyl include, but are not limited to,hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “mercapto” as used herein, means a —SH group.

The term “nitro” as used herein, means a —NO₂ group.

The term “thio(C₁-C₆)alkyl” as used herein, means a sulfur atom appendedto the parent molecular moiety through a (C₁-C₆)alkyl group, as definedherein. Representative examples of thio(C₁-C₆)alkyl include, but are notlimited to, thiomethyl, 2-thioethyl, 3-thiopropyl, and 4-thiobutyl.

The term “—NR_(A)R_(B)” as used herein, means two groups, R_(A) andR_(B) appended to the parent molecular moiety through a nitrogen atom.R_(A) and R_(B) are each independently hydrogen, (C₁-C₆)alkyl, or(C₁-C₆)alkylcarbonyl. Representative examples of —NR_(A)R_(B) include,but are not limited to, amino, methylamino, dimethylamino, acetylamino,and acetylmethylamino.

The term “NR_(A)R_(B)(C₁-C₆)alkoxy” as used herein, mean a NR_(A)R_(B)group attached to the parent molecular moiety through a (C₁-C₆)alkoxygroup.

The term “NR_(A)R_(B)(C₁-C₆)alkyl” as used herein, mean a NR_(A)R_(B)group attached to the parent molecular moiety through a (C₁-C₆)alkylgroup.

The term “(NR_(A)R_(B))carbonyl” as used herein, means a NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein.

Representative examples of (NR_(A)R_(B))carbonyl include, but are notlimited to, aminocarbonyl, (methylamino)carbonyl,(dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.

The term “—NR_(C)R_(D)” as used herein, means two groups, R_(C) andR_(D) appended to the parent molecular moiety through a nitrogen atom.R_(C) and R_(D) are each independently hydrogen, (C₁-C₆)alkyl, or(C₁-C₆)alkylcarbonyl. Representative examples of —NR_(C)R_(D) include,but are not limited to, amino, methylamino, dimethylamino, acetylamino,and acetylmethylamino.

The term “NR_(C)R_(D)(C₁-C₆)alkoxy” as used herein, mean a NR_(C)R_(D)group attached to the parent molecular moiety through a (C₁-C₆)alkoxygroup.

The term “NR_(C)R_(D)(C₁-C₆)alkyl” as used herein, mean a NR_(C)R_(D)group attached to the parent molecular moiety through a (C₁-C₆)alkylgroup.

The term “(NR_(C)R_(D))carbonyl” as used herein, means a NR_(C)R_(D)group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein.

The compounds of the present invention may form boron-oxygen dativebonds following exposure to water, alcohols (ROH, R is alkyl), and diols(ROH, R is hydroxyalkyl) as depicted in Scheme A.

When a boron atom is covalently bonded to an oxygen atom and dativelybonded to a second oxygen atom, the dative bond and covalent bond caninterconvert or form a resonance hybrid as exemplified by structures(1), (2), (3), and (4) in Scheme A. Compounds of the present inventionfollowing exposure to water, alcohols, and diols may exist as neutralcompounds, exemplified by compounds (1)-(4), or as negatively chargedcompounds depicted by compounds (5) and (6), wherein R₁, R₂, R₃, R₄, R₅,R₆, R₇, R₉, R₁₀ and p are as defined in the Summary section herein. Inaddition to oxygen, boron may form dative bonds with sulfur andnitrogen. It is to be understood that the present invention encompassesthe compounds of Formula (I), Formula (IA), Formula (IB), and Formula(IC) that form dative bonds with oxygen, sulfur, and nitrogen including,but not limited to compounds (7)-(12). Suitable counter ions include,but are not limited to, lithium, sodium, potassium, ammonium,tetramethylammonium, tetraethylammonium, methylammonium,dimethylammonium, trimethylammonium, triethylammonium, diethylammonium,ethylammonium, calcium, magnesium, and aluminum.

The compounds of the present invention may form oxygen-linked dimersfollowing exposure to water. Representative dimers of the presentinvention are shown in Scheme B wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₉,R₁₀, and p are as defined in the Summary section herein.

It is to be understood that the present invention encompasses theoxygen-linked dimers of Formula (I), Formula (IA), Formula (IB) andFormula (IC) including, but not limited to,bis((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)diboronicacid andbis((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)diboronicacid.

The compounds of the present invention may also form acyclic and cyclictrimers with exposure to water. Representative acyclic and cyclictrimers of the present invention are shown in Scheme C wherein R₁, R₂,R₃, R₄, R₅, R₆, R₇, R₉, R₁₀ and p are as defined in the Summary sectionherein.

It is to be understood that the present invention encompasses acyclicand cyclic trimers of Formula (I), Formula (IA), Formula (IB) andFormula (IC) including, but not limited to, the acyclic trimers (13) and(14) shown in Scheme C and the cyclic trimers(2R,2′R,2″R)-3,3′,3″-(1,3,5,2,4,6-trioxatriborinane-2,4,6-triyl)tris(2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propan-1-ol)and(2S,2′S,2″S)-3,3′,3″-(1,3,5,2,4,6-trioxatriborinane-2,4,6-triyl)tris(2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propan-1-ol).

The present invention encompasses anhydrides of Formula (I), Formula(IA), Formula (IB) and Formula (IC) formed under dehydrating conditions.Representative anhydrides of the present invention are shown in Scheme Dwherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₉, R₁₀, and p are as defined in theSummary section herein.

It is to be understood that the present invention encompasses theanhydrides of Formula (I), Formula (IA), Formula (IB) and Formula (IC)including, but not limited to,5,5′-((4S,4'S)-oxybis(1,2-oxaborolane-2,4-diyl))bis(3-(4-methoxy-3-propoxyphenyl)pyridine)and5,5′-((4R,4′R)-oxybis(1,2-oxaborolane-2,4-diyl))bis(3-(4-methoxy-3-propoxyphenyl)pyridine).

The compounds of the present invention may form poly- or multi-valentspecies assembled from a single species or from more than one species ofthe present invention. The polymeric constructs can be “homopolymeric”consisting of the same or related constructs, or “hetereropolymeric”consisting of multiple different constructs.

The present invention encompasses compounds that can be formulated withexcipients such that one or more excipients interact with the compoundsof the present invention to afford single, poly-, or multi-valentspecies, including, for example, species such as esters, dimers,trimers, tetramers and higher homologs. For example, compounds ofFormula (I), Formula (IA), Formula (IB) and Formula (IC) may formboron-esters with propylene glycol or hexylene glycol under appropriateconditions. Representative esters of the present invention are shown inScheme E wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₉, R₁₀, and p are asdefined in the Summary section herein.

It is to be understood that the present invention encompassesboron-esters of Formula (I), Formula (IA), Formula (IB) and Formula (IC)including, but not limited to, 1-hydroxypropan-2-yl hydrogen((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,(S)-1-hydroxypropan-2-yl hydrogen((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,(R)-1-hydroxypropan-2-yl hydrogen((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,2-hydroxypropyl hydrogen((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,(S)-2-hydroxypropyl hydrogen((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,(R)-2-hydroxypropyl hydrogen((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,4-hydroxy-2-methylpentan-2-yl hydrogen((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,(S)-4-hydroxy-2-methylpentan-2-yl hydrogen((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,(R)-4-hydroxy-2-methylpentan-2-yl hydrogen((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,4-hydroxy-4-methylpentan-2-yl hydrogen((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,(S)-4-hydroxy-4-methylpentan-2-yl hydrogen((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,(R)-4-hydroxy-4-methylpentan-2-yl hydrogen((R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,1-hydroxypropan-2-yl hydrogen((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,(S)-1-hydroxypropan-2-yl hydrogen((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,(R)-1-hydroxypropan-2-yl hydrogen((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,2-hydroxypropyl hydrogen((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,(S)-2-hydroxypropyl hydrogen((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,(R)-2-hydroxypropyl hydrogen((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,4-hydroxy-2-methylpentan-2-yl hydrogen((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,(S)-4-hydroxy-2-methylpentan-2-yl hydrogen((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,(R)-4-hydroxy-2-methylpentan-2-yl hydrogen((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,4-hydroxy-4-methylpentan-2-yl hydrogen((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,(S)-4-hydroxy-4-methylpentan-2-yl hydrogen((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate,and (R)-4-hydroxy-4-methylpentan-2-yl hydrogen((S)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronate.

The present invention also encompasses cyclic esters formed byinteraction of compounds of Formula (I), Formula (IA), Formula (IB), andFormula (IC) with certain diols that include, but are not limited to,propylene glycol and hexylene glycol. Representative cyclic esters areshown in Scheme F wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₉, R₁₀, and p areas defined in the Summary section herein.

It is to be understood that the present invention encompasses cyclicboron-esters of Formula (I), Formula (IA), Formula (IB) and Formula (IC)including, but not limited to,(2R)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4-methyl-1,3,2-dioxaborolan-2-yl)propan-1-ol,(R)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-((S)-4-methyl-1,3,2-dioxaborolan-2-yl)propan-1-ol,(R)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-((R)-4-methyl-1,3,2-dioxaborolan-2-yl)propan-1-ol,(2R)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan-1-ol,(R)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-((S)-4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan-1-ol,(R)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-((R)-4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan-1-ol,(2S)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4-methyl-1,3,2-dioxaborolan-2-yl)propan-1-ol,(S)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-((S)-4-methyl-1,3,2-dioxaborolan-2-yl)propan-1-ol,(S)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-((R)-4-methyl-1,3,2-dioxaborolan-2-yl)propan-1-ol,(2S)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan-1-ol,(S)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-((S)-4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan-1-ol,and(S)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-((R)-4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan-1-ol.

The salts, esters, anhydrides, dimers, and trimers exemplified inSchemes A-F are prodrugs that can hydrolyze back to the parent compoundsunder aqueous conditions which include in vivo conditions reforming theoxaborole ring.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. By “pharmaceutically acceptable salt” is meant those salts whichare, within the scope of sound medical judgement, suitable for use incontact with the tissues of humans and animals without undue toxicity,irritation, allergic response and the like and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell-known in the art. For example, S. M. Berge et al. describepharmaceutically acceptable salts in detail in J. PharmaceuticalSciences, 1977, 66:1-19, herein incorporated by reference. The salts canbe prepared in situ during the final isolation and purification of thecompounds of the present invention or separately by reacting a free base(basic nitrogen) with a suitable organic or inorganic acid.Representative acid addition salts include, but are not limited toacetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,bicarbonate, p-toluenesulfonate and undecanoate. Also, the basicnitrogen-containing groups can be quaternized with such agents as loweralkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulphuric acid and phosphoric acid and such organic acids as oxalicacid, maleic acid, succinic acid and citric acid.

Compounds of the present invention may exist as stereoisomers wherein,asymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The terms “R” and “S” used herein are configurations asdefined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., 1976, 45: 13-30. In particular, thestereochemistry at the point of attachment of Y and Z, as shown inFormulae (I), (IA), and (IB) may independently be either (R) or (S),unless specifically noted otherwise. The enantiomers of the presentinvention indicated by (R), (S), or * are substantially free of theother enantiomer. “Substantially free” means that the enantiomericexcess is greater than about 90%, preferably greater than about 95%, andmore preferably greater than about 99%. Within the context ofenantiomeric excess, the term “about” means ±1.0%. The symbol *designates a chiral carbon atom as either (R) or (S) stereochemistrydepending on the configuration of substituents around the chiral carbonatom. The present invention contemplates various stereoisomers andmixtures thereof that are specifically included within the scope of thisinvention. Stereoisomers include enantiomers and mixtures ofenantiomers. Individual stereoisomers of compounds of the presentinvention may be prepared synthetically from commercially availablestarting materials which contain asymmetric or chiral centers or bypreparation of racemic mixtures followed by resolution well-known tothose of ordinary skill in the art. These methods of resolution include,but are not limited to, (1) attachment of a chiral auxiliary to amixture of enantiomers, separation of the resulting mixture ofdiastereomers by recrystallization or chromatography and liberation ofthe optically pure product from the auxiliary or (2) direct separationof the mixture of optical enantiomers on chiral chromatographic columns.

Compounds of the present invention not designated (R), (S), or * mayexist as racemates (i.e. 50% (R) and 50% (S)) or as a mixture of twoenantiomers wherein one enantiomer is in excess. For example,enantiomeric mixtures may include the (R) enantiomer in 51% and the (S)enantiomer in 49% or vice versa or any combination of (R) and (S) otherthan the racemic mixture of 50% (R) and 50% (S). The present inventionincludes racemates and enantiomeric mixtures of the compounds of thepresent invention.

Compounds of the present invention may exist in different stableconformational forms which may be separable. Torsional asymmetry due torestricted rotation about an asymmetric single bond, for example becauseof steric hindrance or ring strain, may permit separation of differentconformers. The compounds of the present invention further include eachconformational isomer of compounds of Formulae (I), (IA), (IB), and (IC)and mixtures thereof.

Tautomers may exist in the compounds of the present invention and arespecifically included within the scope of the present invention. Theterm “tautomer,” as used herein, means a proton shift from one atom of amolecule to another atom of the same molecule wherein two or morestructurally distinct compounds are in equilibrium with each other.Compounds of the present invention may exist as tautomers. The presentinvention contemplates tautomers due to proton shifts from one atom toanother atom of the same molecule generating two or more distinctcompounds that are in equilibrium with each other.

The compounds of the present invention may be isolated and used per seor in the form of their pharmaceutically acceptable salts. In accordancewith the present invention, compounds with multiple basic nitrogen atomscan form salts with varying number of equivalents (“eq.”) of acid. Itwill be understood by practitioners that all such salts are within thescope of the present invention.

Compounds of the present invention may exist in more than one crystalform. Polymorphs of compounds of Formulae (I), (IA), (IB), and (IC) andsalts thereof (including solvates and hydrates) form part of thisinvention and may be prepared by crystallization of a compound of thepresent invention under different conditions. For example, usingdifferent solvents or different solvent mixtures for recrystallization;crystallization at different temperatures; various modes of cooling,ranging from very fast to very slow cooling during crystallization.Polymorphs may also be obtained by heating or melting a compound of thepresent invention followed by gradual or fast cooling. The presence ofpolymorphs may be determined by solid probe nuclear magnetic resonance(NMR) spectroscopy, infrared (IR) spectroscopy, differential scanningcalorimetry, powder X-ray diffraction or such other techniques.

This invention also includes isotopically-labeled compounds, which areidentical to those described by Formulae (I), (IA), (IB), and (IC), butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, sulfur, chlorine, iodine, and fluorine, such as ²H,³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ³⁶Cl, ¹²⁵I, ¹²⁹I ¹⁸F, and ¹⁹Frespectively. Certain isotopically-labeled compounds of the presentinvention, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated (i.e., ³H), and carbon-14 (i.e., ¹⁴C),isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H), can afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements and, hence, may bepreferred in some circumstances. Isotopically labeled compounds of thepresent invention can generally be prepared by carrying out theprocedures disclosed in the schemes and/or in the Examples below, bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

In particular, the present invention includes deuterated compounds ofFormula (I), (IA), (IB), and (IC). Any of the hydrogens contained on thecompounds of the present invention may be exchanged for deuterium.Representative examples of deuterated compounds of the present inventioninclude, but are not limited to, the compounds listed below wherein D isdeuterium.

All patents, patent applications, and literature references cited in thespecification are herein incorporated by reference in their entirety.

Compounds of the present invention were named by Chemdraw Professionalversion 15.0 or 16.0 or were given names which appeared to be consistentwith Chemdraw nomenclature.

The present invention encompasses compounds of Formulae (I), (IA), (IB),and (IC) when prepared by synthetic processes or by metabolic processes.Preparation of the compounds of the invention by metabolic processesinclude those occurring in the human or animal body (in vivo) orprocesses occurring in vitro.

The present invention also contemplates pharmaceutically activemetabolites formed by in vivo biotransformation of compounds of Formulae(I), (IA), (IB), and (IC). The term pharmaceutically active metabolite,as used herein, refers to a compound formed by the in vivobiotransformation of compounds of Formulae (I), (IA), (IB), and (IC). Athorough discussion of biotransformation is provided in (Goodman andGilman's, The Pharmacological Basis of Therapeutics, seventh edition,MacMillan Publishing Company, New York, N.Y., (1985)).

Compounds of the present invention may be synthesized by syntheticroutes that include processes analogous to those well-known in thechemical arts, particularly in light of the description containedherein. The starting materials are generally available from commercialsources or are readily prepared using methods well known to thoseskilled in the art (e.g., prepared by methods generally described inLouis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch derorganischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, includingsupplements (also available via the Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below providepotential routes for synthesizing the compounds of the present inventionas well as intermediates for preparing compounds of the presentinvention. For a more detailed description of the individual reactionsteps, see the Examples section below. Those skilled in the art willappreciate that other synthetic routes may be used to synthesize theinventive compounds. Although specific starting materials and reagentsare depicted in the schemes and discussed below, other startingmaterials and reagents can be substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

In the preparation of compounds of the present invention protection ofremote functionalities such as carboxylic acids, amines, and/or hydroxygroups of intermediates may be necessary. The need for such protectionwill vary depending on the nature of the remote functionality and theconditions of the preparation methods. Suitable amino-protecting groups(NH-PG) include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC),benzyloxycarbonyl (Cbz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc).Similarly, a “hydroxy-protecting group” refers to a substituent of ahydroxy group that blocks or protects the hydroxy functionality.Suitable hydroxyl-protecting groups (O-PG) include for example, allyl,acetyl, silyl, benzyl, para-methoxybenzyl, trityl, and the like.Carboxylic acid protecting groups include alkyl esters such as methy,ethyl, propyl, and tert-butyl. The need for such protection is readilydetermined by one skilled in the art. For a general description ofprotecting groups and their use, see T. W. Greene, Protective Groups inOrganic Synthesis, John Wiley & Sons, New York, 1991.

The reactions are performed in a solvent appropriate to the reagents andmaterials employed and suitable for the transformations being effected.It will be understood by those skilled in the art of organic synthesisthat the functionality present on the molecule should be consistent withthe transformations proposed. This will sometimes require a judgment tomodify the order of the synthetic steps or to select one particularprocess scheme over another in order to obtain a desired compound of theinvention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene and Wuts (Protective Groups In Organic Synthesis,Wiley and Sons, 1999). Suitable protecting groups include, but are notlimited to, tert-butoxycarbonyl (BOC), trimethylsilylethanesulfonamide(SES), benzyloxycarbonyl (CBZ) and benzyl (Bn) protecting groups. TheBOC protecting group may be removed by treatment with an acid such astrifluoroacetic acid or concentrated hydrochloric acid and the SESprotecting group may be removed with a fluoride salt, such as cesiumfluoride or tetrabutylammonium fluoride. The CBZ and Bn protectiongroups may be removed by catalytic hydrogenation. Additional suitableprotecting groups for hydroxy substituents include, but are not limitedto, t-butyldimethylsilyl (TBDMS), tetra-hydropyranyl (THP), or isopropyl(i-Pr) protecting groups. The TBDMS and THP protecting groups may beremoved by treatment with an acid such as acetic acid or hydrochloricacid while the i-Pr protecting group may be removed by aluminumtrichloride.

Isolation and purification of the compounds and intermediates describedherein can be effected, if desired, by any suitable separation orpurification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography,thick-layer chromatography, preparative low, medium, or high-pressureliquid chromatography, or a combination of these procedures. Specificillustrations of suitable separation and isolation procedures can be hadby reference to the Examples herein below. However, other equivalentseparation or isolation procedures could also be used.

The compounds of the invention may be prepared by any method known inthe art for the preparation of compounds of analogous structure. Inparticular, the compounds of the invention can be prepared by theprocedures described by reference to the Schemes that follow, or by thespecific methods described in the Examples, or by similar processes toeither.

The skilled person will appreciate that the experimental conditions setforth in the schemes that follow are illustrative of suitable conditionsfor effecting the transformations shown, and that it may be necessary ordesirable to vary the precise conditions employed for the preparation ofcompounds of Formulae (I), (IA), (IB), and (IC). It will be furtherappreciated that it may be necessary or desirable to carry out thetransformations in a different order from that described in the schemes,or to modify one or more of the transformations, to provide the desiredcompound of the invention.

The derivatives of Formulae (I), (IA), (IB), and (IC) can be prepared bythe procedures described in the general methods presented below or byroutine modifications thereof. The present invention also encompassesone or more of these processes for preparing the derivatives of Formulae(I), (IA), (IB), and (IC), in addition to any novel intermediates usedtherein. The person skilled in the art will appreciate that thefollowing reactions may be heated thermally or under microwaveirradiation.

The routes below, including those mentioned in the Examples andPreparations, illustrate methods of synthesising compounds of Formulae(I), (IA), (IB), and (IC). The skilled person will appreciate that thecompounds of the invention, and intermediates thereto, could be made bymethods other than those specifically described herein, for example byadaptation of the methods described herein, for example by methods knownin the art. Suitable guides to synthesis, functional groupinterconversions, use of protecting groups, etc., are for example:“Comprehensive Organic Transformations” by RC Larock, VCH PublishersInc. (1989); Advanced Organic Chemistry” by J. March, Wiley Interscience(1985); “Designing Organic Synthesis” by S Warren, Wiley Interscience(1978); “Organic Synthesis—The Disconnection Approach” by S Warren,Wiley Interscience (1982); “Guidebook to Organic Synthesis” by RK Mackieand DM Smith, Longman (1982); “Protective Groups in Organic Synthesis”by TW Greene and PGM Wuts, John Wiley and Sons, Inc. (1999); and“Protecting Groups” by PJ Kocienski, Georg Thieme Verlag (1994); and anyupdated versions of said standard works.

In addition, the skilled person will appreciate that it may be necessaryor desirable at any stage in the synthesis of compounds of the inventionto protect one or more sensitive groups, so as to prevent undesirableside reactions. In particular, it may be necessary or desirable toprotect alcohol, amino or carboxylic acid groups. The protecting groupsused in the preparation of the compounds of the invention may be used ina conventional manner. See, for example, those described in ‘Greene'sProtective Groups in Organic Synthesis’ by Theodora W Greene and PeterGM Wuts, fifth edition, (John Wiley and Sons, 2014), incorporated hereinby reference, which also describes methods for the removal of suchgroups.

In the general synthetic methods below, unless otherwise specified, thesubstituents are as defined above with reference to the compounds ofFormula (I) above. Where ratios of solvents are given, the ratios are byvolume unless otherwise specified.

The compounds of the invention may be prepared by any method known inthe art for the preparation of compounds of analogous structure. Inparticular, the compounds of the invention can be prepared by theprocedures described by reference to the Schemes that follow, or by thespecific methods described in the Examples, or by similar processes toeither. The skilled person will appreciate that the experimentalconditions set forth in the schemes that follow are illustrative ofsuitable conditions for effecting the transformations shown, and that itmay be necessary or desirable to vary the precise conditions employedfor the preparation of compounds of Formula (I).

According to the first process, compounds of Formula (1D) (where R₁, R₂,R₃, R₄, R₅, R₆, R₇, R₉, R₁₀, and p are as defined in the Summary sectionherein and v=0, 1, 2, 3, 4, 5) may be prepared from compounds of Formula(II) and (III) as illustrated by Scheme 1.

In Scheme 1, compounds of the Formula (II), wherein R₁₄ is a suitableprotecting group (preferably TBS), are converted to a compound ofFormula (III) wherein R₁₅ is boronic acid (preferably) or4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Bpin) by treatment with asuitable hydroborating source such as catecolborane orbis(pinacolato)diboron, in the presence of a suitable catalyst(bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) or(1.5-cycloocatdiene)(methoxy)iridium(I) dimer) and ligand(ethylenebis(diphenylphosphine), in a suitable solvent such as DCE orTHF at an appropriate temperature (15° C. to 70° C.). A skilled personalso knows alternative methods for hydroboration of alkenes areachievable using alternative reagents, solvents and temperatures. Acompound of Formula (III) is converted into a compound of Formula (1D)under aqueous acidic conditions, treating with a suitable acid (aceticor hydrochloric) at a suitable temperature. It is well understood by askilled person that a compound of the Formula (III) is prepared andisolated as described above or prepared in situ without isolation in asequential reaction strategy leading to a compound of Formula (1D). Inthe case of compounds of Formula (III) and (1D) lead to the presence ofa chiral center, it is well understood by a skilled person that theindividual enantiomers can be obtained using a suitable separationmethod such as HPLC or SFC chromatography to afford both the (+) and (−)enantiomers of compounds of Formula (III) and (1D). It is wellunderstood by a skilled person that an individual enantiomer of acompound of Formula (III) and (1D) is prepared and isolated as describedabove or isolated using an alternative separation technique such as HPLCor SFC using a suitable chiral stationary phase eluting with a suitablemobile phase as determined to be necessary to isolate the requiredenantiomers.

According to a second process, compounds of Formula (1E) or (1F) may beprepared from Formula (II) as illustrated in Scheme 2.

In Scheme 2, compounds of Formula (1E) or (1F) may be prepared in asimilar manner as in Scheme 1 using suitable chiral ligands such as(S,S)-[2-(4′-i-propyloxazolin-2-yl)ferrocynyl]diphenylphosphine or(R,R)-[2-(4′-i-propyloxazolin-2-yl)ferrocynyl]diphenylphosphine leadingto chiral compounds of Formula (IV). A person of skill in the art knowsthat chiral hydroboration strategies can use alternative chiral ligands,catalysts, boron sources, solvents and temperature combinations. It iswell understood by a skilled person that a compound of the Formula (IV)can be prepared and isolated as described above or prepared in situwithout isolation in a sequential reaction strategy leading to acompound of Formula (1E) or (1F). A skilled person also knows thatcompounds of Formula (1E) or (1F) can be further enriched throughcrystallization techniques or chiral chromatography (HPLC or SFC) usinga suitable chiral stationary phase eluting with a suitable mobile phaseas determined to be necessary to isolate the required enantiomers.

According to a third process, compounds of Formula (1G) may be preparedfrom Formula (II) as illustrated in Scheme 3.

In Scheme 3, compounds of Formula (II) are converted to compounds ofFormula (V) when treated with a halogenating agent such as pyridiniumtribromide, in a suitable solvent, such as DCM, at an appropriatetemperature such as 0° C. A skilled person also knows that alternativemethods for specifically introducing a suitable halogen group such as Brare achievable using alternative reagents, solvents and temperatures.Compounds of Formula (VI) can be synthesized by this method or by thereaction of compounds of Formula (V) using DBU with a suitable solvent,such as DCM, at a suitable temperature, such as 25° C. Compounds ofFormula (VI) can be converted to compounds of Formula (VII) (whereR₁₅=Bpin) using Miyaura borylation conditions. Typical boronate esterformation conditions comprise of Pd(dppf)Cl₂.DCM and potassium acetatewith bispinacolatoboron in 1,4-dioxane at a suitable temperature, suchas 55° C. A compound of Formula (VII) can be converted into a compoundof Formula (1G) under aqueous acidic conditions, treating with asuitable acid (acetic or hydrochloric) at a suitable temperature.

Compounds of Formula (II) may be prepared from compounds of Formulae(VIII), (IX), (X) and (XI) as illustrated by Scheme 4.

In Scheme 4, compounds of Formula (X), wherein R₁₇ is chloro, bromo oriodo may be prepared from compounds of Formula (VIII) and (IX) using asuitable organometallic cross-coupling reaction such as Suzukicross-coupling reaction preceded if necessary by a boronic acid or esterformation. Typical Suzuki cross-coupling conditions comprise of apalladium catalyst containing suitable phosphine ligands, in thepresence of an inorganic base, in aqueous dioxane or methanol, atelevated temperatures either thermally or under microwave irradiation.Preferred conditions comprise Pd(OAc)₂, Pd(dppf)Cl₂ or Pd(PPh₃)₄ witheither sodium, cesium or potassium carbonate in aqueous dioxane ormethanol at from room temperature to 120° C. A skilled person knows thatorganometallic cross-coupling reaction strategies can be used involvingalternative metals, catalysts, ligands, bases, solvents and temperaturecombinations. Typical boronic ester formation conditions comprise ofPd(dppf)Cl₂ and potassium acetate with bispinacolatodiboron withcompounds of Formula (VIII), where R₁₆=chloro, bromo or iodo, in dioxaneat reflux. Compounds of Formula (VIII) may also be obtained commerciallyor be synthesized by those skilled in the art according to theliterature or by analogy with the methods described herein.

Compounds of Formula (II) may be prepared from compounds of Formula (X)and (XI), (where R₁₈=boronic acid or Bpin) through an organometalliccross-coupling reaction, similar to the ones previously described. Askilled person knows that alternative organometallic cross-couplingreaction strategies can also be used involving alternative metals,catalysts, ligands, bases, solvents and temperature combinations.Preferred Suzuki conditions comprise of Pd(dppf)Cl₂ with potassiumcarbonate and potassium acetate in aqueous dioxane from room temperatureto 120° C.

Alternatively, compounds of Formula (II) may be prepared from compoundsof Formulae (VIII), (IX), (XI) and (XII), in a reverse sequence of thatin Scheme 4, illustrated by Scheme 5.

Compounds of Formula (XII) may be prepared from compounds of Formula(XI) (where R₁₈=boronic acid or pinacol) and (IX) (where R₁₇ is chloro,bromo or iodo) using an organometallic cross-coupling reaction asdescribed in Scheme 4. Preferred conditions comprise of Pd(dppf)Cl₂ withpotassium carbonate in aqueous dioxane from room temperature to 120° C.Compounds of Formula (XI) may be synthesized by those skilled in the artaccording to the literature or by analogy with the methods describedherein. Compounds of Formula (XII) may be converted to compounds ofFormula (II) using a similar method as previously described in Scheme 4,a Suzuki cross-coupling reaction preceded if necessary by a boronic acidor ester formation. A skilled person knows that alternativeorganometallic cross-coupling reaction strategies can also be usedinvolving alternative metals, catalysts, ligands, bases, solvents andtemperature combinations.

According to a sixth process, compounds of Formula (1H) may be preparedfrom Formula (XIII) and (XIV) as illustrated in Scheme 6. IDC-77.C3

Compounds of Formula (1H), where A is carbon or nitrogen, may beprepared in an analogous manner as compounds of Formula (1D), (1E) or(1F) as described in Schemes 1-5. It is well understood by a skilledperson that the individual enantiomers can be obtained using a suitableseparation method such as HPLC or SFC chromatography to afford both the(+) and (−) enantiomers of compounds of Formula (XIV) and (1H). It isalso well understood by a skilled person that an individual enantiomerof a compound of Formula (XIV) and (1H) is prepared and isolated asdescribed above or isolated using an alternative separation techniquesuch as HPLC or SFC using a suitable chiral stationary phase elutingwith a suitable mobile phase as determined to be necessary to isolatethe required enantiomers. Additionally, compounds of Formula (1H) inwhich the central ring is replaced by a substituted 5-memberedheterocycle (exemplified by Y, in Formula (1)) can also be synthesizedin an analogous manner by one skilled in the art.

The compounds and processes of the present invention will be betterunderstood in connection with the following Examples which are intendedas an illustration of and not a limitation upon the scope of theinvention as defined in the appended claims.

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are: Ac is acetyl; AcOH is acetic acid;Ac₂O is acetic anhydride; Adam's catalyst is platinum (IV) oxide; Br₂ isbromine; n-BuLi is n-butyl lithium; ° C. is degrees celcius; CDCl₃ isdeutero-chloroform; CD₃OD is deuteromethanol; CO₂ is carbon dioxide;Cs₂CO₃ is cesium carbonate; b is chemical shift; DAST isN,N-Diethylamino-S,S-difluorosulfinium tetrafluoroborate; DBU is1,8-Diazabicyclo[5.4.0]undec-7-ene; DCE is 1,2-dichloroethane; DCM isdichloromethane or methylene chloride; DEA is diethylamine; DMAP is4-dimethylaminopyridine; DMF is dimethylformamide; DMSO is dimethylsulfoxide; DMSO-d₆ is deuterodimethylsulfoxide; Et₂O is diethyl ether;EtOAc is ethyl acetate; EtOH is ethanol; Et₃N is triethylamine; Fe isiron; g is gram; HCl is hydrochloric acid; HCO₂H is formic acid; HMTA ishexamethylenetetramine; HPLC is high pressure liquid chromatography; H₂is hydrogen; H₂O is water; h is hours; Hr is hour; Hz is hertz; IPA isisopropyl alcohol; IPAm: is isopropylamine; [Ir(COD)Cl]₂ isbis(1,5cyclooctadiene)diiridium(I) dichloride; [Ir(COD)OMe]₂ is(1.5-cycloocatdiene)(methoxy)iridium(I) dimer; K₂CO₃ is potassiumcarbonate; K₃PO₄ is potassium phosphate tribasic; KBr is potassiumbromide; KMnO₄ is potassium permanganate; KOAc is poatssium acetate; Lis liter; LCMS is liquid chromatography mass spectrometry; LDA islithium diisopropylamide; LiHMDS is lithium bis(trimethylsilyl)amide;LiOH is lithium hydroxide monohydrate; LTMP is lithiumtetramethylpiperidine; M is molar; m-CPBA is meta-chloroperoxybenzoicacid; MeCN is acetonitrile; MeOH is methanol; MeNH₂ is methyl amine; mgis milligram; MgSO₄ is magnesium sulphate; MHz is mega Hertz; min isminutes; mL is milliliter; mm is millimeter; mmol is millimole; mol ismole; MS m/z is mass spectrum peak; MTBE is tert-butyl methyl ether;MsCl is mesyl chloride; NaBH₄ is sodium borohydride; Na₂CO₃ is sodiumcarbonate; NaOH is sodium hydroxide; NaOMe is sodium methoxide; Na₂SO₄is sodium sulphate; NBS is N-bromo succinimide; NH₃ is ammonia; NH₄Cl isammonium chloride; NH₂OH.HCl is hydroxylamine hydrochloride; NH₄OH isammonium hydroxide; nM is nanomolar; PCI₅ is phosphorus pentachloride;Pd/C is palladium on carbon; Pd(dppf)Cl₂ is [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(dppf)Cl₂DCM is[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II), complexwith dichloromethane; Pd(dppf)-tBu is [1,1′-bis(di-t-butylphosphino)ferrocene]dichloropalladium(II); Pd(OAc)₂ is palladium acetate; PPh₃ istriphenylphosphine; pet. ether is petroleum ether; pH is power ofhydrogen; Pin₂B₂ is bis(pinacolato)diboron; PinBO-iPr is2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; psi is pounds persquare inch; ppm is parts per million; POCl₃ is phosphorus oxychloride;PrOH is 1-propanol; PtO₂ is platinum (IV) oxide; rt is room temperature,RT is retention time; SEM-Cl is 2-(trimethylsilyl)ethoxymethyl chloride;SFC is supercritical fluid chromatography; TBS is t-butyldimethylsilyl;TBS-Cl is t-butyldimethylsilyl chloride; tBu₃P is tri-t-butylphosphine;TFA is trifluoroacetic acid; TFAA is trifluoroacetic anhydride; TiCl₄ istitanium tetrachloride; TfO is trifluoromethanesulfonyl; Tf₂O istrifluoromethanesulfonic anhydride; pTsOH is p-toluenesulfonic acid;Turbo Grignard is isopropylmagnesium chloride lithium chloride complexsolution; Xantphos is 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene;XPhos-Pd-G2 isChloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II).

¹H and ¹⁹F Nuclear magnetic resonance (NMR) spectra were in all casesconsistent with the proposed structures. Characteristic chemical shifts(6) are given in parts-per-million downfield from tetramethylsilane (for¹H-NMR) and upfield from trichloro-fluoro-methane (for ¹⁹F NMR) usingconventional abbreviations for designation of major peaks: e.g. s,singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets;dt, doublet of triplets; td, triplet of doublets; m, multiplet; br,broad. The following abbreviations have been used for common solvents:CDCl₃, deuterochloroform; DMSO-d₆, deuterodimethylsulphoxide; and CD₃OD,deuteromethanol. Where appropriate, tautomers may be recorded within theNMR data; and some exchangeable protons may not be visible.

Mass spectra, MS (m/z), were recorded using either electrosprayionization (ESI) or atmospheric pressure chemical ionization (APCI).

Where relevant and unless otherwise stated the m/z data provided are forisotopes ¹⁹F, ³⁵Cl, ⁷⁹Br and ¹²⁷I.

Wherein preparative TLC or column chromatography (silica) has been used,one skilled in the art may choose any combination of appropriatesolvents to purify the desired compound.

Specific rotations based on the equation [α]=(100−α)/(I·c) are reportedas unitless numbers where the concentration c is in g/100 mL and thepath length l is in decimeters. The units of the specific rotation,(deg·mL)/g·dm) are implicit and are not included with the reportedvalue.

The following are analytical and preparative chromatography methods usedfor the analysis and purification of compounds of the invention.

Preparative SFC Methods

Prep SFC Method A: Column: Chiralpak IC-H, 250 mm×30 mm, 5μ; MobilePhase—Isocratic conditions: CO₂/EtOH, 60/40 (v/v); Flow rate: 65 mL/min

Prep SFC Method B: Column: Lux Amylose-1 250 mm×30 mm, 5μ; MobilePhase—Isocratic conditions: CO₂/MeOH+0.2% (7N ammonia in MeOH) 80/20(v/v); Flow rate: 150 mL/min

Prep SFC Method C: Column: Chiralpak IC-H, 250 mm×50 mm, 5μ; MobilePhase—Isocratic conditions: CO₂/IPA 85/15 (v/v); Flow rate: 250 mL/min

Prep SFC Method D: Column: Chiralcel OJ, 250 mm×30 mm, 5μ; MobilePhase—Isocratic conditions: CO₂/IPA, 65/35 (v/v); Flow rate: 50 mL/min)Prep SFC Method E: Column: Daicel Chiralpak AD, 250 mm×30 mm, 5μ; MobilePhase—Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 60/40 (v/v); Flowrate: 50 mL/min

Prep SFC Method F: Column: Daicel Chiralpak IC, 250 mm×30 mm, 5μ; MobilePhase—Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 60/40 (v/v); Flowrate: 200 mL/min)

Prep SFC Method G: Column: Daicel Chiralpak AD, 250 mm×50 mm, 10μ;Mobile Phase—Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 55/45 (v/v);Flow rate: 200 mL/min

Prep SFC Method H: Column: Chiralpak IC-H, 250 mm×30 mm, 5μ; MobilePhase—Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 75/25 (v/v); Flowrate: 200 mL/min

Prep SFC Method I: Column: Chiralpak IC, 250 mm×30 mm, 10μ; MobilePhase—Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 60/40 (v/v); Flowrate: 60.0 mL/min

Prep SFC Method J: Column: Chiralpak IC 250 mm×30 mm, 10μ; MobilePhase—Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 80/20 (v/v); Flowrate: 60 mL/min

Prep SFC Method K: Column: Chiralpak AD, 250 mm×30 mm, 5μ; MobilePhase—Isocratic conditions: CO₂/MeOH (0.1% NH₄OH), 75/25 (v/v); Flowrate: 50.0 mL/min

Prep SFC Method L: Column: Chiralpak AD, 250 mm×30 mm, 10μ; MobilePhase—Isocratic conditions: CO₂/MeOH (0.1% NH₄OH), 75/25 (v/v); Flowrate: 200.0 mL/min

Prep SFC Method M: Column: Chiralpak IC, 250 mm×30 mm, 5μ; MobilePhase—Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 55/45 (v/v); Flowrate: 50.0 mL/min

Prep SFC Method N: Column: Chiralpak IC, 250 mm×30 mm, 5μ; MobilePhase—Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 75/25 (v/v); Flowrate: 60.0 mL/min

Prep SFC Method 0: Column: Daicel Chiralpak AD, 250 mm×50 mm, 10μ;Mobile Phase—Isocratic conditions: CO₂/MeOH, 60/40 (v/v); Flow rate: 200mL/min

Prep SFC Method P: Column: Chiralcel OJ-H, 250 mm×30 mm, 5μ; MobilePhase—Isocratic conditions: CO₂/EtOH (0.1% NH₄OH), 85/15 (v/v); Flowrate: 50 mL/min

Prep SFC Method Q: Column: Daicel Chiralpak AD, 250 mm×30 mm, 5μ; MobilePhase—Isocratic conditions: CO₂/IPA (0.1% NH₄OH), 75/25 (v/v); Flowrate: 60 mL/min

Prep SFC Method R: Column: Chiral Technologies AD-H, 250 mm×21 mm, 5μ;Mobile Phase—Isocratic conditions: CO₂/MeOH (0.2% NH₄OH), 80/20 (v/v);Flow rate: 75 mL/min

Prep SFC Method S: Column: Princeton PPU, 250 mm×30 mm, 5μ; MobilePhase—Isocratic conditions: CO₂/MeOH, 80/20 (v/v); Flow rate: 80 mL/min

Analytical SFC Methods

Analytical SFC Method A: Column: Chiralpak IC, 250 mm×4.6 mm, 5μ; MobilePhase A: CO₂, Mobile Phase B: EtOH (0.05% isopropylamine); Gradient:A:B=65:35; Flow rate: 2.5 mL/min

Analytical SFC Method B: Column: Lux Amylose-1, 250 mm×4.6 mm, 5μ;Mobile Phase A: CO₂, Mobile Phase B: MeOH (0.2% MeNH₂); Gradient Elution(time, % A, % B): (0 min, 95% A, 5% B), (1.0 min, 95% A, 5% B), (9.0min, 40% A, 60% B), (10 min, 95% A, 5% B); Flow rate: 3.0 mL/min

Analytical SFC Method C: Column: Chiralpak IC-3, 150 mm×4.6 mm, 3μ;Mobile Phase A: CO₂, Mobile Phase B: IPA (0.05% DEA); Gradient Elution(time, % A, % B): (0 min, 95% A, 5% B), (5.5 min, 60% A, 40% B), (8.5min, 60% A, 40% B), (10 min, 95% A, 5% B), Flow rate: 2.5 mL/min

Analytical SFC Method D: Column: Chiralpak AD-3, 150 mm×4.6 mm, 3μ;Mobile Phase A: CO₂, Mobile Phase B: EtOH (0.05% DEA); Gradient Elution(time, % A, % B): (0 min, 95% A, 5% B), (5.5 min, 60% A, 40% B), (8.5min, 60% A, 40% B), (10 min, 95% A, 5% B), Flow rate: 2.5 mL/min

Analytical SFC Method E: Column: Chiralpak IC-3, 150 mm×4.6 mm, 3μ;Mobile Phase A: CO₂, Mobile Phase B: EtOH (0.05% DEA); Gradient Elution(time, % A, % B): (0 min, 95% A, 5% B), (5.5 min, 60% A, 40% B), (8.5min, 60% A, 40% B), (10 min, 95% A, 5% B), Flow rate: 2.5 mL/min

Analytical SFC Method F: Column: Chiralpak AD-3, 50 mm×3.0 mm, 3μ;Mobile Phase—Isocratic conditions: CO₂/EtOH (0.05% DEA), 60/40 (v/v);Flow rate: 2.0 mL/min

Analytical SFC Method G: Column: Chiralpak AD-3, 150 mm×4.6 mm, 3μ;Mobile phase A: CO₂, Mobile Phase B: MeOH (0.05% DEA); Gradient Elution(time, % A, % B): (0 min, 95% A, 5% B), (5.0 min, 60% A, 40% B), (7.5min, 60% A, 40% B), (10 min, 95% A, 5% B), Flow rate: 2.5 mL/min

Analytical SFC Method H: Column: Chiralcel OJ-3, 100 mm×4.6 mm, 3μ;Mobile Phase A: CO₂, Mobile Phase B: EtOH (0.05% DEA); Gradient Elution(time, % A, % B): (0 min, 95% A, 5% B), (5.0 min, 60% A, 40% B), (7.5min, 60% A, 40% B), (8.5 min, 95% A, 5% B), Flow rate: 2.8 mL/min

Analytical SFC Method I: Column: Chiralpak IC-3, 150 mm×4.6 mm, 3μ;Mobile Phase A: CO₂, Mobile Phase B: EtOH; Gradient Elution (time, % A,% B): (0 min, 95% A, 5% B), (5.5 min, 60% A, 40% B), (8.5 min, 60% A,40% B), (10 min, 95% A, 5% B), Flow rate: 2.5 mL/min

Analytical SFC Method J: Column: Chiralpak AD-3, 150 mm×4.6 mm, 3μ;Mobile Phase A: CO₂, Mobile Phase B: EtOH (0.05% DEA); Gradient Elution(time, % A, % B): (0 min, 95% A, 5% B), (5.0 min, 60% A, 40% B), (7.5min, 60% A, 40% B), (10 min, 95% A, 5% B), Flow rate: 2.5 mL/min

Analytical SFC Method K: Column: Chiral Technologies AD-H, 100 mm×4.6mm, 3μ; Mobile Phase A: CO₂, Mobile Phase B: MeOH (0.2% NH₄OH); GradientElution (time, % A, % B): (5 min, 60% A, 40% B, [Flow rate: 1.5 mL/min

Analytical SFC Method L: Column: ChiralCel OJ-H, 150 mm×4.6 mm, 5μ;Mobile Phase A: CO₂, Mobile Phase B: EtOH (0.05% DEA); Gradient Elution(time, % A, % B): (0 min, 95% A, 5% B), (5.0 min, 60% A, 40% B), (8.5min, 60% A, 40% B), (10 min, 95% A, 5% B), Flow rate: 2.5 mL/min

Analytical SFC Method M: Column: Chiral Tech IG, 250 mm×4.6 mm, 5μ;Mobile Phase A: CO₂, Mobile Phase B: MeOH (0.2% 7N NH3 in MeOH);Gradient Elution (time, % A, % B): (0 min, 95% A, 5% B), (1.0 min, 95%A, 5% B), (9.0 min, 40% A, 60% B), (9.5 min, 40% A, 60% B), (10 min, 95%A, 5% B), Flow rate: 3.0 mL/min

Analytical SFC Method N: Column: Chiralcel OJ-H 250 mm×4.6 mm, 5μ;Mobile Phase A: CO₂, Mobile Phase B: IPA (0.05% IPAm), Gradient Elution:B in A from 10% to 40% in 10 minutes, Flow rate: 2.5 mL/min

Analytical SFC Method 0: Column: ChiralPak AY-3 150 mm×4.6 mm, 3μ;Mobile Phase: A: CO₂, Mobile Phase B: Methanol (0.05% DEA); GradientElution: (time, % A, % B): (0 min, 95% A, 5% B), (5.5 min, 60% A, 40%B), (8.5 min, 60% A, 40% B) (10 min, 95% A, 5% B), Flow rate: 2.5 mL/min

Analytical SFC Method P: Column: Chiralcel OJ-3 100 mm×4.6 mm, 3μ;Mobile Phase: A: CO₂, Mobile Phase B: Methanol (0.05% DEA); GradientElution: (time, % A, % B): (0 min, 95% A, 5% B), (5.5 min, 60% A, 40%B), (7.5 min, 60% A, 40% B) (10 min, 95% A, 5% B), Flow rate: 2.8 mL/min

Analytical SFC Method Q: Column: ChiralCel OD-3, 150 mm×4.6 mm, 3μ;Mobile Phase A: CO₂, Mobile Phase B: EtOH (0.05% DEA); Gradient Elution(time, % A, % B): (0 min, 95% A, 5% B), (5.0 min, 60% A, 40% B), (5.5min, 95% A, 5% B), (7 min, 95% A, 5% B), Flow rate: 2.5 mL/min

Analytical SFC Method R: Column: Chiralpak AD-3, 100 mm×4.6 mm, 3μ;Mobile Phase—Isocratic conditions: CO₂/EtOH (0.05% DEA), 60/40 (v/v);Flow rate: 2.08 mL/min

Analytical SFC Method S: Column: Chiral Technologies OJ-H, 100 mm×4.6mm, 5μ; Mobile Phase—Isocratic conditions: CO₂/EtOH (0.2% NH₄OH), 95/5(v/v); Flow rate: 3.0 mL/min

Analytical SFC Method T: Column: Chiralpak IC, 100 mm×4.6 mm, 3μ; MobilePhase A: CO₂, Mobile Phase B: EtOH (0.05% DEA); Gradient Elution (time,% A, % B): (0 min, 95% A, 5% B), (0.5 min, 95% A, 5% B) (4.5 min, 60% A,40% B), (7.0 min, 60% A, 40% B), (9.5 min, 95% A, 5% B), Flow rate: 1.5mL/min

Analytical SFC Method U: Column: Lux Amylose-2, 100 mm×4.6 mm, 5μ;Mobile Phase A: CO₂, Mobile Phase B: MeOH (0.2% NH₄OH); Gradient Elution(time, % A, % B): (0 min, 70% A, 30% B), (5.0 min, 70% A, 30% B); Flowrate: 1.5 mL/min

Analytical SFC Method V: Column: Chiral Technologies AD-H, 100 mm×4.6mm, 5μ; Mobile Phase A: CO₂, Mobile Phase B: MeOH (0.2% Ammoniumhydroxide); Gradient Elution (time, % A, % B): (0 min, 85% A, 15% B) (10min, 85% A, 15% B). Flow rate: 1.5 mL/min

Analytical SFC Method W: Column: Chiral Tech IG, 250 mm×4.6 mm, 5μ;Mobile Phase A: CO₂, Mobile Phase B: EtOH; Gradient Elution (time, % A,% B): (0 min, 95% A, 5% B), (1.0 min, 95% A, 5% B), (9.0 min, 40% A, 60%B), (9.5 min, 40% A, 60% B), (10 min, 95% A, 5% B), Flow rate: 3.0mL/min

Analytical SFC Method X: Column: ChiralPak AY, 150 mm×4.6 mm, 3μ; MobilePhase A: CO₂, Mobile Phase B: EtOH (0.05% DEA); Gradient Elution (time,% A, % B): (0 min, 95% A, 5% B), (5.0 min, 40% A, 60% B), (7.5 min, 40%A, 60% B), (10 min, 95% A, 5% B), Flow rate: 2.5 mL/min

Analytical SFC Method Y: Column: Chiral Tech OJ-H, 100 mm×4.6 mm, 5μ;Mobile Phase A: CO₂, Mobile Phase B: MeOH (0.2% NH₄OH); Gradient Elution(time, % A, % B): (0 min, 95% A, 5% B), (10 min, 95% A, 5% B), Flowrate: 1.5 mL/min

Analytical SFC Method Z: Column: Chiralcel OJ-3, 150 mm×4.6 mm, 3μ;Mobile Phase A: CO₂, Mobile Phase B: EtOH (0.05% DEA); Gradient Elution(time, % A, % B): (0 min, 95% A, 5% B), (5 min, 60% A, 40% B), (7.5 min,60% A, 40% B), (10 min, 95% A, 5% B), Flow rate: 2.5 mL/min

Analytical SFC Method AA: Column: ChiralPak AD-3 100 mm×4.6 mm, 3μ;Mobile Phase: A: CO₂, Mobile Phase B: MeOH (0.05% DEA); GradientElution: (time, % A, % B): (0 min, 60% A, 40% B), Flow rate: 2.8 mL/min

Analytical SFC Method BA: Column: Chiralpak IC-3, 150 mm×4.6 mm, 3μ;Mobile Phase A: CO₂, Mobile Phase B: IPA (0.05% DEA); Gradient Elution(time, % A, % B): (0 min, 95% A, 5% B), (5 min, 60% A, 40% B), (7.5 min,60% A, 40% B), (10 min, 95% A, 5% B), Flow rate: 2.5 mL/min

Analytical SFC Method CA: Column: Lux Cellulose 100 mm×4.6 mm, 5μ;Mobile Phase: A: CO₂, Mobile Phase B: MeOH (0.2% NH₄OH); GradientElution: (time, % A, % B): (0 min, 70% A, 30% B), (5 min, 70% A, 30% B),Flow rate: 1.5 mL/min

Analytical SFC Method DA: Column: Lux Cellulose-2, 150 mm×4.6 mm, 5μ;Mobile Phase A: CO₂, Mobile Phase B: MeOH (0.05% DEA); Gradient Elution(time, % A, % B): (0 min, 95% A, 5% B), (5.0 min, 60% A, 40% B), (8.5min, 60% A, 40% B), (10 min, 95% A, 5% B), Flow rate: 2.5 mL/min

Analytical SFC Method EA: Column: Chiralcel OJ-3, 150 mm×4.6 mm, 3μ;Mobile Phase—Isocratic conditions: CO₂/EtOH (0.05% DEA), 60/40 (v/v);Flow rate: 2.5 mL/min

Analytical SFC Method FA: Column: ChiralPak AD-3, 250 mm×4.6 mm, 5μ;Mobile Phase A: CO₂, Mobile Phase B: EtOH (0.05% IPAm); Gradient Elution(time, % A, % B): (0 min, 65% A, 35% B), Flow rate: 2.5 mL/mi

Analytical SFC Method GA: Column: Chiral Tech IC, 250 mm×4.6 mm, 5μ;Mobile Phase A: CO₂, Mobile Phase B: IPA (0.2% NH₃ in MeOH); GradientElution (time, % A, % B): (0 min, 95% A, 5% B), (1 min, 95% A, 5% B), (9min, 40% A, 60% B), (9.5 min, 40% A, 60% B), (10 min, 95% A, 5% B), Flowrate: 2.5 mL/min

Preparative HPLC Methods

Prep HPLC Method A: Column: Xtimate C18, 150 mm×25 mm, 5μ; Mobile PhaseA: water (0.05% NH₄OH v/v), Mobile Phase B MeCN; B %: 18%-58%, 12 min;Flow rate: 25 mL/min

Prep HPLC Method B: Column: Phenomenex XB-C18, 250 mm×21.2 mm, 5μ;Mobile Phase A: water (0.1% HCO₂H), Mobile Phase B: MeCN (0.1% HCO₂H);Gradient Elution (time, % A, % B): (0 min, 95% A, 5% B), (1.5 min, 95%A, 5% B), (10.0 min, 0% A, 100% B), (11 min, 0% A, 100% B), (12.5 min,95% A, 5% B); Flow rate: 27 mL/min

Prep HPLC Method C: Column: Waters Atlantis C18, 50 mm×4.6 mm, 5μ;Mobile Phase A: water (0.05% TFA), Mobile Phase B: MeCN (0.05% TFA);Gradient Elution (time, % A, % B): (0 min, 95% A, 5% B), (4 min, 5% A,95% B), (5 min, 5% A, 95% B); Flow rate: 2 mL/min

Prep HPLC Method D: Column: Xtimate C18, 150 mm×25 mm, 5μ; Mobile PhaseA: water (0.05% ammonium hydroxide), Mobile Phase B: MeCN; B %: 25% to65% in 12 min, Flow rate: 25 ml/min

Prep HPLC Method E: Column: Waters Xbridge, 150 mm×25 mm, 5μ; MobilePhase A: water (10 mM NH₄HCO), Mobile Phase B: MeCN; B %: 20%-50%,12 min

Prep HPLC Method F: Column: Phenomenex luna C18, 250 mm×80 mm, 10μ;Mobile Phase A: water (0.1% TFA), Mobile Phase B: MeCN; B %: 1%-25%, 20min

Prep HPLC Method G: Column: Phenomenex Synergi Max-RP, 250 mm×80 mm,10μ; Mobile Phase A: water (0.1% TFA), Mobile Phase B: MeCN; B %:10%-40%, 20 min

Prep HPLC Method H: Column: Boston Green ODS, 150 mm×30 mm, 5μ; MobilePhase A: water (0.225% HCO₂H), Mobile Phase B: MeCN; B %: 5%-53%, 11min, Flow rate: 25 mL/min

Prep HPLC Method I: Column: Agela Durashell C18, 150 mm×25 mm, 5μ;Mobile Phase A: water (0.225% HCO₂H), Mobile Phase B: MeCN; B %: 9%-39%,12 min, flow rate: 25 mL/min

Prep HPLC Method J: Column: Phenomenex Gemini C18, 250 mm×50 mm, 10μ;Mobile Phase A: water (0.05% ammonium hydroxide), Mobile Phase B: MeCN;B %: 5%-25%, 15 min, flow rate: 100 mL/min

Prep HPLC Method K: Column: Agela Durashell C18, 150 mm×25 mm, 5μ;Mobile Phase A: water (0.225% HCO₂H), Mobile Phase B: MeCN; B %: 0%-32%,11 min, Flow rate 25 mL/min

Prep HPLC Method L: Column: Xtimate C18,150 mm×25 mm, 5μ; Mobile PhaseA: water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; B %: 15%-55%, 12 min,Flow rate: 25 mL/min

Prep HPLC Method M: Column: Agela Durashell 150 mm×25 mm, 5μ; MobilePhase A: water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; B %: 30%-60%,2.5 min, Flow rate: 25 mL/min

Prep HPLC Method N: Column: Phenomenex luna C18, 250 mm×80 mm, 10μ;Mobile Phase A: water (0.1% TFA), Mobile Phase B: MeCN; B %: 25%-55%, 20min, Flow rate: 25 mL/min

Prep HPLC Method 0: Column: Agela Durashell, 150 mm×25 mm, 5μ; MobilePhase A: water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; B %: 25%-55%, 10min, Flow rate: 25 mL/min

Prep HPLC Method P: Column: Agela Durashell, 150 mm×25 mm, 5μ; MobilePhase A: water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; B %: 30%-60%, 10min, flow rate: 25 mL/min

Prep HPLC Method Q: Column: Agela Durashell, 150 mm×25 mm, 5μ; MobilePhase A: water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; B %: 23%-53%, 10min, flow rate: 25 mL/min

Prep HPLC Method R: Column: Phenomenex Gemini C18, 250 mm×50 mm, 10μ;Mobile Phase A: Water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; GradientElution (time, % A, % B): (0 min, 90% A, 10% B), (15 min, 60% A, 40% B),(18 min, 0% A, 100% B), Flow rate: 110 mL/min)

Prep HPLC Method S: Column: Phenomenex Gemini C18, 250 mm×50 mm, 10μ;Mobile Phase A: Water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; GradientElution (time, % A, % B): (0 min, 80% A, 20% B), (15 min, 60% A, 40% B),(18 min, 0% A, 100% B), Flow rate: 110 mL/min

Prep HPLC Method T: Column: Phenomenex Gemini C18, 250 mm×50 mm, 10μ;Mobile Phase A: Water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; B %:20%-40%, 15 min, flow rate 110 ml/min

Prep HPLC Method U: Column: Phenomenex Gemini C18, 250 mm×50 mm, 10μ;Mobile Phase A: Water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; GradientElution (time, % A, % B): (0 min, 75% A, 25% B), (15 min, 55% A, 45% B),(18 min, 0% A, 100% B), Flow rate: 110 mL/min

Prep HPLC Method V: Column: Phenomenex Synergi Max-RP, 150 mm×50 mm,10μ; Mobile Phase A: Water (0.225% HCO₂H), Mobile Phase B: MeCN; B %:0%-30%, 25 min, flow rate 120 mL/min

Prep HPLC Method W: Column: Xtimate C18, 150 mm×25 mm, 5μ; Mobile PhaseA: Water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; B %: 17%-57%, 12 min,Flow rate: 25 mL/min

Prep HPLC Method X: Column: Agela Durashell C18, 150 mm×30 mm, 5μ;Mobile Phase A: Water, Mobile Phase B: MeCN; Gradient Elution (time, %A, % B): (0 min, 82% A, 18% B), (10 min, 42% A, 58% B), (18 min, 0% A,100% B), Flow rate: 25 mL/min

Prep HPLC Method Y: Column: Boston Green ODS, 150 mm×30 mm, 5μ; MobilePhase A: water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; B %: 45%-65%, 9min, Flow rate 25 mL/min

Prep HPLC Method Z: Column: Phenomenex Gemini C18, 250 mm×50 mm, 10μ;Mobile Phase A: Water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; GradientElution (time, % A, % B): (0 min, 80% A, 20% B), (15 min, 60% A, 40% B),(18 min, 0% A, 100% B), Flow rate: 110 mL/min

Prep HPLC Method AA: Column: Gemini C18, 15 mm×21.2 mm, 5μ; Mobile PhaseA: water (0.1% HCO2H) Mobile Phase B: MeCN (0.1% HCO₂H); B % 25%-35%; 25mL/min

Prep HPLC Method BA: Column: Agela Durashell C18, 150 mm×30 mm, 5μ;Mobile Phase A: water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; B %:20%-55%, 15 min, Flow rate: 25 mL/min

Prep HPLC Method CA: Column: Phenomenex Gemini C18, 250 mm×50 mm, 10μ;Mobile Phase A: Water (0.05% NH₄OH v/v), Mobile Phase B: MeCN; GradientElution (time, % A, % B): (0 min, 75% A, 25% B), (15 min, 55% A, 45% B),(18 min, 0% A, 100% B); Flow rate: 110 mL/min

EXAMPLES Preparation 1:3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3,4-dimethoxyphenyl)pyridine

To a solution of3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine(Preparation 2, 1.6 g, 3.13 mmol) in EtOAc (50 mL) was added Pd/C (0.5g, 10% loading). The mixture was stirred under H₂ (5 psig) at 20° C. forabout 3 h. The mixture was filtered and concentrated to afford3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3,4-dimethoxyphenyl)pyridine(1.2 g), which was used directly without further purification. ¹H NMR(CDCl₃, 400 MHz): δ 8.69 (d, J=7.6 Hz, 1H), 8.48 (s, 1H), 7.78 (s, 1H),7.32 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.12 (d, J=1.6 Hz, 1H), 7.04-7.01(m, 1H), 4.15-4.20 (m, 1H), 4.00 (d, J=8.4 Hz, 6H), 3.75-3.79 (m, 1H),2.10 (s, 12H), 1.31 (d, J=11.2 Hz, 9H), 1.15 (d, J=12.8 Hz, 1H), 0.88(d, J=8.8 Hz, 1H), 0.01-0.02 (m, 6H). LCMS m/z=514 [MH]⁺.

Preparation 2:3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine

A solution of3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine(Preparation 37, 0.83 g, 1.79 mmol), Pd(dppf)Cl₂.DCM (73 mg, 89 umol),KOAc (263 mg, 2.68 mmol) and Pin₂B₂ (CAS 73183-34-3, 681 mg, 2.68 mmol)in 1,4-dioxane (10 mL) was heated to 55° C. under N₂ for 12 h. Themixture was concentrated and the residue was purified by columnchromatography (silica) and eluted with pet. ether/EtOAc (3:1) to afford3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine(900 mg, 98%). ¹H NMR (CDCl₃, 400 MHz): δ 8.74 (s, 1H), 8.71 (s, 1H),8.03 (s, 1H), 7.13-7.16 (m, 1H), 7.09 (s, 1H), 6.98 (d, J=8.4 Hz, 1H),5.90 (s, 1H), 4.97 (s, 2H), 3.96 (s, 3H), 3.94 (s, 3H). LCMS m/z=512[MH]⁺.

Preparation 3:3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine(3.8 g, 95%) was prepared in an analogous manner to Preparation 1 using3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine(Preparation 4, 4.0 g, 7.6 mmol) which was used without furtherpurification.

Preparation 4:3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine(7.5 g, 97%) was prepared in an analogous manner to Preparation 2 using3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine(Preparation 38, 7.0 g, 14.6 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 8.69-8.73(m, 2H), 8.03 (s, 1H), 7.14 (dd, J=2.0, 8.4 Hz, 1H), 7.10 (s, 1H), 6.97(d, J=8.4 Hz, 1H), 5.90 (s, 1H), 4.97 (s, 2H), 4.18 (q, J=7.2 Hz, 2H),3.93 (s, 1H), 1.51 (t, J=7.2 Hz, 3H), 1.33 (s, 12H), 0.83 (s, 9H), 0.08(s, 6H).

Preparation 5:3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine

To a solution of3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(Preparation 8, 4.00 g, 7.41 mmol) in EtOAc (100 mL) was added Pd/C (1.0g, 10% loading) under N₂. The mixture was stirred under H₂ (14 psig) atabout 25° C. for about 3 h. The mixture was filtered and concentrated toafford3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(3.44 g, 86%), which was used without further purification.

Preparation 6:(R)-(3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronicacid

Method A:

To a mixture of3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(Preparation 50, 50.00 g, 120.9 mmol), [Ir(COD)Cl]₂ (CAS 12112-67-3,2.03 g, 3.02 mmol) and(S,S)-[2-(4′-i-propyloxazolin-2-yl)ferrocynyl]diphenylphosphine (CAS163169-29-7, 3.20 g, 6.65 mmol) was added anhydrous THF (403 mL). Themixture was stirred for about 15 min at about 20° C. under N₂. The flaskwas chilled in an ice water bath until the solution temperature wasabout 0° C. Catecholborane (181.48 mL, 181 mmol, 1.0 M in THF) was addeddropwise over 1 h. Once the catecholborane was added the flask wasremoved from the cooling bath and stirred at about 20° C. for about 3 h.The mixture was quenched with a dropwise addition of methanol (25 mL) atabout 0° C. (ice bath). The solution was removed from the ice bath andstirred about 30 min. The solution was concentrated to afford(R)-(3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronicacid (88 g), which is used directly without further purification. LCMSm/z=460 [MH]⁺.

Method B:

To a solution of Turbo Grignard (180 mL, 117 mmol, 1.3 M in THF) wasadded 1,4-dioxane (19 mL) and stirred at about 20° C. for about 1 h. Tothe mixture was added slowly a solution of(R)-3-(1-((tert-butyldimethylsilyl)oxy)-3-iodopropan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(Preparation 42, 46.8 g, 86.5 mmol) in anhydrous THF (270 mL), which wasstirred at about 20° C. for about 20 min. A solution of trimethyl borate(96.4 mL, 865 mmol) in THF (107 mL) was added drop wise and stirred atabout 20° C. for about 30 min. The mixture was concentrated andpartitioned between water (500 mL) and EtOAc (200 mL). The aqueous layerwas extracted with EtOAc (3×100 mL). The combined EtOAc layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography (silica) and eluted withheptanes/EtOAc (80:20 to 0:100) followed by EtOAc/MeOH (100:0 to 90:10)to afford(R)-(3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronicacid (29.0 g, 73%). ¹H NMR (CD₃OD, 400 MHz): δ 8.51 (d, J=2.3 Hz, 1H),8.30 (d, J=2.0 Hz, 1H), 7.85 (br s, 1H), 7.14-7.17 (m, 2H), 7.03 (d,J=7.8 Hz, 1H), 4.00 (t, J=6.6 Hz, 2H), 3.85 (s, 3H), 3.70-3.80 (m, 2H),3.27 (br s, 2H), 3.07-3.14 (m, 1H), 1.76-1.85 (m, 2H), 1.10-1.33 (m,2H), 1.03 (t, J=7.81 Hz, 3H), 0.79 (s, 9H), −0.08 (d, J=12.9 Hz, 6H).LCMS m/z=460 [MH]⁺.

Preparation 7:(S)-(3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronicacid

To a mixture of3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(Preparation 50, 1.0 g, 2.42 mmol), [Ir(COD)Cl]₂ (CAS 12112-67-3, 44.2mg, 0.06 mmol) and(R,R)-[2-(4′-i-propyloxazolin-2-yl)ferrocynyl]diphenylphosphine (CAS541540-70-9, 58.2 mg, 0.12 mmol) was added anhydrous THF (8.1 mL). Themixture was stirred at about 20° C. for about 10 min. The reaction wascooled to about 0° C. and catecholborane (6.04 mL, 6.04 mmol, 1.0 M inTHF) was added dropwise. The reaction was warmed to about 20° C. andstirred for about 8 h. The reaction was cooled to about 5° C. andquenched with MeOH. The mixture was concentrated and purified by columnchromatography (silica) and eluted with DCM/MeOH (100:0 to 90:10) toafford(S)-(3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronicacid (889 mg, 80%). ¹H NMR (CD₃OD, 400 MHz): δ 8.51 (d, J=2.3 Hz, 1H),8.30 (d, J=2.0 Hz, 1H), 7.85 (br s, 1H), 7.14-7.17 (m, 2H), 7.03 (d,J=7.8 Hz, 1H), 4.00 (t, J=6.6 Hz, 2H), 3.85 (s, 3H), 3.70-3.80 (m, 2H),3.27 (br s, 2H), 3.07-3.14 (m, 1H), 1.76-1.85 (m, 2H), 1.10-1.33 (m,2H), 1.03 (t, J=7.81 Hz, 3H), 0.79 (s, 9H), −0.08 (d, J=12.9 Hz, 6H).LCMS m/z=460 [MH]⁺.

Preparation 8:3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine

3-(1-Bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(Preparation 39, 5.60 g, 11.37 mmol), Pd(dppf)Cl₂ (415.98 mg, 568.50umol), Pin₂B₂ (4.33 g, 17.06 mmol) and KOAc (2.23 g, 22.74 mmol) indioxane (100 mL) was heated to about 60° C. under N₂ for about 16 h. Themixture was filtered and concentrated. The residue was purified bycolumn chromatography (silica) and eluted with pet. ether/EtOAc (5:1) toafford3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(6.10 g, 99%). ¹H NMR (CDCl₃, 400 MHz): δ 8.70-8.73 (m, 2H), 8.03 (t,J=2.0 Hz, 1H), 7.14 (dd, J=2.0, 8.4 Hz, 1H), 7.10 (s, 1H), 6.97 (d,J=8.4 Hz, 1H), 5.90 (s, 1H), 4.97 (s, 2H), 4.06 (t, J=6.8 Hz, 2H), 3.93(s, 1H), 1.87-1.96 (m, 2H), 1.33 (s, 12H), 1.08 (t, J=7.6 Hz, 3H), 0.83(s, 9H), 0.07 (s, 6H).

Preparation 9:3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-isopropoxy-4-methoxyphenyl)pyridine

Bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) (CAS 12148-71-9, 96 mg,0.15 mmol) and ethylenebis(diphenylphosphine) (CAS, 1663-45-2, 116 mg,0.29 mmol) in anhydrous DCE (10 mL) were stirred for about 15 min underN₂ at about 15° C.3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-isopropoxy-4-methoxyphenyl)pyridine(Preparation 51, 600 mg, 1.45 mmol) was added to the mixture under N₂ atabout 15° C. After stirring for about 5 min,4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS 25015-63-9, 913 mg, 7.13mmol) was added at about 70° C. and stirred for an additional 15 min.The reaction was quenched with MeOH and concentrated. The residue waspurified by column chromatography (silica) and eluted with pet.ether:EtOAc (100:0 to 85:15) to give afford3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-isopropoxy-4-methoxyphenyl)pyridine(750 mg, 96%). LCMS m/z=542 [MH]⁺.

Preparation 10:3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine(750 mg, 95%) was prepared in an analogous manner to Preparation 9 using3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine(Preparation 52, 600 mg, 1.46 mmol). LCMS m/z=540 [MH]⁺.

Preparation 11:3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine(2.0g, 81%) was prepared in an analogous manner to Preparation 9 using3-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)pyridine(Preparation 53, 2.0 g, 3.8 mmol). LCMS m/z=658 [MH]⁺.

Preparation 12:3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine(12.0 g, 97%) was prepared in an analogous manner to Preparation 9 using3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine(Preparation 54, 10.0 g, 18.4 mmol). LCMS m/z=671 [MH]⁺.

Preparation 13:3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine(700 mg, 89%) was prepared in an analogous manner to Preparation 9 using3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine(Preparation 55, 600 mg, 1.4 mmol). LCMS m/z=433 [MH]⁺.

Preparation 14:tert-butyl(2-(3′-(3-fluoropropoxy)-4′-methoxy-[1,1′-biphenyl]-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propoxy)dimethylsilane

tert-butyl(2-(3′-(3-fluoropropoxy)-4′-methoxy-[1,1′-biphenyl]-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propoxy)dimethylsilanewas prepared in an analogous manner to Preparation 9 using3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(3-fluoropropoxy)-4-methoxyphenyl)pyridine(Preparation 56).

Preparation 15:3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine(300 mg, 46%) was prepared in an analogous manner to Preparation 9 using3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine(Preparation 57, 361 mg, 1.13 mmol). LCMS m/z=578 [MH]⁺.

Preparation 16:3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridine(650 mg, 75%) was prepared in an analogous manner to Preparation 9 using3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridine(Preparation 58, 660 mg, 1.58 mmol). LCMS m/z=546 [MH]⁺.

Preparation 17:3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridine(800 mg, 77%) was prepared in an analogous manner to Preparation 9 using3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridine(Preparation 59, 800 mg, 1.8 mmol). LCMS m/z=562 [MH]⁺.

Preparation 18:3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine(2.0 g, 85%) was prepared in an analogous manner to Preparation 9 using3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine(Preparation 60, 1.80 g, 4.31 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 8.56 (t,J=1.7 Hz, 1H), 8.44 (d, J=2.0 Hz, 1H), 7.71 (m, 1H), 6.88 (d, J=7.5 Hz,1H), 6.73 (d, J=11.5 Hz, 1H), 4.10 (q, J=7.0 Hz, 2H), 3.90 (s, 3H),3.68-3.75 (m, 2H), 3.07-3.14 (m, 1H), 1.47 (t, J=7.0 Hz, 3H), 1.22-1.29(m, 2H), 1.09 (d, J=13.1 Hz, 12H), 0.81 (s, 9H), −0.06 (d, J=6.5 Hz,6H). LCMS m/z=546 [MH]⁺.

Preparation 19:3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridine(2.05 g, 73%) was prepared in an analogous manner to Preparation 9 using3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridine(Preparation 61, 2.17 g, 5.0 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 8.44 (m,2H), 7.63 (t, J=2.0 Hz, 1H), 6.95 (s, 1H), 6.77 (s, 1H), 4.06 (q, J=7.0Hz, 2H), 3.89 (s, 3H), 3.64-3.74 (m, 2H), 3.06-3.13 (m, 1H), 1.45 (t,J=7.0 Hz, 3H), 1.23-1.29 (m, 2H), 1.08 (d, J=13.6 Hz, 12H), 0.79 (s,9H), −0.08 (d, J=6.8 Hz, 6H).

Preparation 20:3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine(4.0 g, 86%) was prepared in an analogous manner to Preparation 9 using3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine(Preparation 62, 6 g, 8.3 mmol). LCMS m/z=560 [MH]⁺.

Preparation21:3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridine(2.25 g, 88%) was prepared in an analogous manner to Preparation 9 using3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridine(Preparation 63, 2.0 g, 4.5 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 8.61 (d,J=2.2 Hz, 1H), 8.57 (d, J=2.1 Hz, 1H), 7.73 (t, J=2.1 Hz, 1H), 7.24 (d,J=8.0 Hz, 1H), 7.09-7.12 (m, 2H), 6.61 (t, J=75.3 Hz, 1H), 4.05 (t,J=6.5 Hz, 2H), 3.67-3.77 (m, 2H), 3.09-3.16 (m, 1H), 2.16 (s, 2H),1.84-1.93 (2H), 1.06-1.11 (m, 15H), 0.81 (s, 9H), −0.07-−0.05 (d, J=5.8Hz, 6H). LCMS m/z=578 [MH]⁺.

Preparation 22:5′-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-3-fluoro-5-methoxy-6-propoxy-2,3′-bipyridine

5′-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-3-fluoro-5-methoxy-6-propoxy-2,3′-bipyridine(4.02 g, quant.) was prepared in an analogous manner to Preparation 9using5′-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-3-fluoro-5-methoxy-6-propoxy-2,3′-bipyridine(Preparation 64, 3.1 g, 7.17 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 9.03 (s,1H), 8.45 (d, J=2.3 Hz, 1H), 8.13-8.15 (m, 1H), 6.95 (d, J=11.3 Hz, 1H),4.12 (t, J=7.0 Hz, 2H), 3.92 (s, 3H), 3.68-3.76 (m, 2H), 3.09-3.16 (m,1H), 1.85-1.94 (m, 2H), 1.22-1.29 (m, 2H), 1.10 (d, J=11.5 Hz, 12H),1.05 (t, J=7.5 Hz, 3H), 0.81 (s, 9H), −0.07-−0.06 (d, J=7.5 Hz, 6H).LCMS m/z=561 [MH]⁺.

Preparation 23:5′-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-6-methoxy-5-propoxy-3,3′-bipyridine

5′-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-6-methoxy-5-propoxy-3,3′-bipyridine(2.55 g, 81%) was prepared in an analogous manner to Preparation 9 using5′-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-6-methoxy-5-propoxy-3,3′-bipyridine(Preparation 65, 2.4 g, 5.8 mmol). LCMS m/z=543 [MH]⁺.

Preparation 24:5-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-2-methylpyridine

5-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-2-methylpyridine(700 mg, 91%) was prepared in an analogous manner to Preparation 9 using5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-2-methylpyridine(Preparation 66, 590 mg, 1.43 mmol). LCMS m/z=542 [MH]⁺.

Preparation 25:4-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidine

4-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidine(0.94 g, 59%) was prepared in an analogous manner to Preparation 9 using4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidine(Preparation 67, 1.27 g, 2.63 mmol). ¹H NMR (CDCl₃, 400 MHz): δ8.17-8.19 (m, 1H), 8.10 (d, J=2.1 Hz, 1H), 7.42 (s, 1H), 6.97 (d, J=8.6Hz, 1H), 4.12-4.16 (m, 2H), 3.95 (s, 3H), 3.79-3.89 (m, 2H), 3.31-3.37(m, 1H), 1.90-1.99 (m, 2H), 1.23-1.29 (m, 2H), 1.13 (s, 6H), 1.10 (t,J=7.5 Hz, 3H), 1.05 (s, 6H), 0.80-0.82 (s, 9H), −0.04 (t, J=3.1 Hz, 3H),−0.08 (t, J=3.1 Hz, 3H). LCMS m/z=611 [MH]⁺.

Preparation 26:2-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-6-(3-ethoxy-4-methoxyphenyl)pyrazine

2-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-6-(3-ethoxy-4-methoxyphenyl)pyrazine(720 mg, 43%) was prepared in an analogous manner to Preparation 9 using2-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-6-(3-ethoxy-4-methoxyphenyl)pyrazine(Preparation 68, 1.26 g, 3.1 mmol). LCMS m/z=529 [MH]⁺.

Preparation 27:2-(6-(1-borono-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)aceticacid

Ethyl2-(6-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate(Preparation 28, 758 mg, 1.21 mmol) was dissolved in MeCN (10 mL) andwater (10 mL). To the solution was added LiOH.H₂O (101 mg, 2.41 mmol) inportions. The mixture was stirred at about 25° C. for about 1 h. Themixture was concentrated. The reaction mixture was used directly in thenext step without further purification. LCMS m/z=519 [MH]⁺.

Preparation 28: ethyl2-(6-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate

Ethyl2-(6-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate(437 mg, 70%) was prepared in an analogous manner to Preparation 9 usingethyl2-(6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate(Preparation 69, 500 mg, 0.99 mmol). LCMS m/z=629 [MH]⁺.

Preparation 29:4-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidine

4-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidine(1.0 g, 58%) was prepared in an analogous manner to Preparation 9 using4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidine(Preparation 70, 1.4 g, 2.5 mmol). LCMS m/z=687 [MH]⁺.

Preparation 30: methyl(Z)-2-(2′-cyano-4′-methoxy-3′-propoxy-[1,1′-biphenyl]-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate

A mixture of methyl(Z)-2-(2′-cyano-4′-methoxy-3′-propoxy-[1,1′-biphenyl]-3-yl)-3-(((trifluoromethyl)sulfonyl)oxy)acrylate(Preparation 40, 15.00 g, 30.03 mmol), Pd(dppf)Cl₂ (1.10 g, 1.50 mmol),Pin₂B₂ (11.44 g, 45.05 mmol) and KOAc (4.42 g, 45.05 mmol) in1,4-dioxane (200 mL) was stirred at about 80° C. for about 2 h under N₂.The mixture was filtered and concentrated. The residue was purified bycolumn chromatography (silica) and eluted with pet. ether/EtOAc (5:1) toafford methyl(Z)-2-(2′-cyano-4′-methoxy-3′-propoxy-[1,1′-biphenyl]-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate(13.6 g, 94%). ¹H NMR (CDCl₃, 400 MHz): δ 7.52 (s, 1H), 7.49-7.47 (m,1H), 7.42-7.40 (m, 2H), 7.14-7.11 (m, 2H), 6.30 (s, 1H), 4.18-4.14 (m,2H), 3.89 (s, 3H), 3.83 (s, 3H), 1.90-1.81 (m, 2H), 1.25 (s, 12H), 1.06(t, J=3.6 Hz, 3H).

Preparation 31:2-(4-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-6-(4-methoxy-3-propoxyphenyl)pyridine

2-(4-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-6-(4-methoxy-3-propoxyphenyl)pyridine(140 mg, 12%) was prepared in an analogous manner to Preparation 9 using2-(4-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-6-(4-methoxy-3-propoxyphenyl)pyridine(Preparation 71, 900 mg, 2.10 mmol). LCMS m/z=556 [MH]⁺.

Preparation 32:(E)-3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-2-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine

A solution of 2,2,6,6-tetramethylpiperidine (CAS 768-66-1, 1.08 mL, 6.41mmol) in THF (2.5 mL) was cooled to about 0° C. (ice bath) under N₂.N-BuLi (2.56 mL, 6.41 mmol, 2.5 M in hexanes) was added dropwise to thesolution and stirred for about 30 min at about 0° C. A solution of2,2′-(ethane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)(Preparation 149, 1810 mg, 6.41 mmol) in THF (2 mL) was added dropwise,which was stirred for about 5 min before cooling to about −78° C. Asolution of2-((tert-butyldimethylsilyl)oxy)-1-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)ethan-1-one(Preparation 75, 666 mg, 1.60 mmol) in THF (3.0 mL) added dropwise andstirred under N₂ at about −78° C. for about 1 h. The reaction was placedin an ice bath and stirred for an additional hour. The reaction wasquenched with water and diluted with EtOAc. The EtOAc was separated,washed with brine and dried over MgSO₄. The solution was filtered andconcentrated. The residue was purified by column chromatography (silica)and eluted with heptane/EtOAc (9:1) to afford(E)-3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-2-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(400 mg, 45%). LCMS m/z=554 [MH]⁺.

Preparation 33: ethyl2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propanoate

To a mixture of ethyl2-(6-bromopyridin-2-yl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propanoate(Preparation 110, 249 mg, 0.625 mmol) and2-(4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 114, 357 mg, 1.22 mmol) in 1,4-dioxane (8.5 mL) was added asolution of K₃PO₄ in water (2.0 M, 0.625 mL, 1.25 mmol). The mixture wasdegassed using N₂ at about 20° C. for about 10 min.Bis(tri-t-butylphosphine)palladium(0) (CAS 53199-31-8, 16.0 mg, 0.03mmol) was added and the mixture was allowed to stir at about 20° C. for2 h. The mixture was diluted with EtOAc, dried over Na₂SO₄, filtered,and concentrated. The residue was purified by column chromatography(silica) and eluted with heptane/EtOAc (100:0 to 0:100) to afford ethyl2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propanoate(134 mg, 44%). ¹H NMR (CDCl₃, 400 MHz,): δ 7.40-7.56 (m, 1H), 7.23-7.38(m, 4H), 7.07-7.13 (m, 4H), 6.96 (d, J=8.6 Hz, 2H), 5.33 (s, 1H),4.02-4.22 (m, 7H), 3.93 (s, 6H), 1.83-2.08 (m, 4H), 1.71 (s, 4H),1.49-1.67 (m, 9H), 1.37 (s, 1H), 1.17-1.29 (m, 19H), 1.09 (t, J=7.4 Hz,7H). LCMS m/z=399 [MH]⁺.

Preparation 34:5-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-3-(4-methoxy-3propoxyphenyl)pyridazine

5-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-3-(4-methoxy-3-propoxyphenyl)pyridazine(160 mg, 41%) was prepared in an analogous manner to Preparation 9 using5-(3-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-3-(4-methoxy-3-propoxyphenyl)pyridazine(Preparation 72, 300 mg, 0.7 mmol). LCMS m/z=557 [MH]⁺.

Preparation 35:3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine

3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine(0.28 g, 26%) was prepared in an analogous manner to Preparation 9 using3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine(Preparation 73, 0.8 g, 1.93 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 8.36 (s,1H), 8.22 (s, 1H), 6.92 (d, J=8.3 Hz, 1H), 6.75-6.78 (m, 1H), 6.73 (d,J=2.0 Hz, 1H), 4.08 (q, J=7.0 Hz, 2H), 3.91 (s, 3H), 3.74-3.78 (m, 1H),3.64-3.68 (m, 1H), 3.38-3.46 (m, 1H), 2.29 (s, 3H), 1.45 (t, J=7.0 Hz,3H), 1.22-1.29 (m, 2H), 1.03-1.08 (m, 12H), 0.79 (s, 9H), −0.11-−0.08(m, 6H). LCMS m/z=542 [MH]+

Preparation 36:4-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-2-(3-ethoxy-4-methoxyphenyl)thiazole

4-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-2-(3-ethoxy-4-methoxyphenyl)thiazole(0.41 g, 39%) was prepared in an analogous manner to Preparation 9 using4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(3-ethoxy-4-methoxyphenyl)thiazole(Preparation 74, 0.8 g, 1.97 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 7.53 (d,J=2.0 Hz, 1H), 7.46 (dd, J=2.0, 8.5 Hz, 1H), 6.91 (s, 1H), 6.89 (d,J=8.3 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 3.88-3.92 (s, 4H), 3.77-3.81 (m,1H), 3.27-3.34 (m, 1H), 1.51 (t, J=7.0 Hz, 3H), 1.27-1.30 (m, 2H), 1.15(d, J=13.6, 12H), 0.85 (s, 9H), −0.03 (s, 6H). LCMS m/z=534 [MH]⁺.

Preparation 37:3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine

To a solution of3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine(Preparation 48, 30.00 g, 77.81 mmol) in DCM (500 mL) was addedpyridinium tribromide (CAS 39416-48-3, 24.9 g, 77.8 mmol) in portions atabout 0° C. The mixture was stirred at about 20° C. for about 1 h andpoured into cold aqueous Na₂SO (100 mL). The mixture was extracted withDCM (3×50 mL). The combined DCM extracts were washed with brine (50 mL),dried over Na₂SO₄ and concentrated. DBU (CAS 6674-22-2, 58.64 mL, 389.1mmol) was added to the above mixture in DCM (500 mL) at about 20° C. Themixture was stirred at about 20° C. for about 16 h and poured intoaqueous NH₄Cl (500 mL). The mixture was extracted with DCM (3×200 mL).The combined DCM extracts were washed with brine (200 mL), dried overNa₂SO₄ and concentrated. The residue was purified by columnchromatography (silica) and eluted with pet. ether/EtOAc (15:1) toafford3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine(27.0 g, 75%). ¹H NMR (CDCl₃, 400 MHz): δ 8.74 (d, J=2.4 Hz, 1H), 8.55(d, J=3.0 Hz, 1H), 7.88 (t, J=2.0 Hz, 1H), 7.13-7.15 (m, 1H), 7.08 (d,J=3.0 Hz, 1H), 6.97 (d, J=7.2 Hz, 1H), 6.57 (s, 1H), 4.76 (s, 2H), 3.96(s, 3H), 3.94 (s, 3H), 0.82 (s, 9H), 0.07 (s, 6H).

Preparation 38:3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine

A mixture of3-(1,2-dibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine(Preparation 47a, 11.0 g, 19.66 mmol) and DBU (CAS 6674-22-2, 5.99 g,39.33 mmol, 5.93 mL) in DCM (150 mL) was stirred at about 25° C. forabout 16 h. The mixture was washed with 1N HCl (300 mL), brine (300 mL),dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby column chromatography (silica) and eluted with pet. ether/EtOAc(10:1) to afford3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine(7.0 g, 74%). ¹H NMR (CDCl₃, 400 MHz): δ 8.74 (d, J=1.6 Hz, 1H), 8.55(d, J=1.6 Hz, 1H), 7.87 (s, 1H), 7.14 (dd, J=1.6, 8.0 Hz, 1H), 7.09 (s,1H), 6.98 (d, J=8.0 Hz, 1H), 6.57 (s, 1H), 4.77 (s, 2H), 4.18 (q, J=6.8Hz, 2H), 3.94 (s, 3H), 1.51 (t, J=6.8 Hz, 3H), 0.82 (s, 9H), 0.08 (s,6H).

Preparation 39:3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine

To a mixture of3-(1,2-ibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(Preparation 47b, 10.0 g, 17.44 mmol) in DCM (150 mL) was added DBU (CAS6674-22-2, 5.26 mL, 34.88 mmol), which was stirred at about 25° C. forabout 16 h under N₂. The mixture was washed with 1N HCl (400 mL), brine(400 mL), dried over Na₂SO₄ and concentrated. The residue was purifiedby column chromatography (silica) and eluted with pet. ether/EtOAc(10:1) to afford3-(1-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(5.60 g, 65%). ¹H NMR (CDCl₃, 400 MHz): δ 8.74 (d, J=2.0 Hz, 1H), 8.55(d, J=1.6 Hz, 1H), 7.87 (s, 1H), 7.13 (dd, J=1.6, 8.4 Hz, 1H), 7.09 (s,1H), 6.98 (d, J=8.0 Hz, 1H), 6.57 (s, 1H), 4.77 (s, 2H), 4.06 (t, J=6.8Hz, 2H), 3.93 (s, 3H), 1.87-1.96 (m, 2H), 1.08 (t, J=7.6 Hz, 3H), 0.82(s, 9H), 0.08 (s, 6H).

Preparation 40: methyl2-(2′-cyano-4′-methoxy-3′-propoxy-[1,1′-biphenyl]-3-yl)-3-(((trifluoromethyl)sulfonyl)oxy)acrylate

To a solution of methyl2-(2′-cyano-4′-methoxy-3′-propoxy-[1,1′-biphenyl]-3-yl)-3-hydroxyacrylate(Preparation 41, 14.5 g, 39.47 mmol) in toluene (500 mL) was added LiOH(11.59 g, 276.27 mmol) in water (30 mL). To the mixture was added Tf₂O(CAS 358-23-8, 15.63 mL, 94.72 mmol) dropwise at about 0° C. The mixturewas stirred at about 0° C. for about 1 h. The reaction was quenched withwater (500 mL) and extracted with EtOAc (2×500 mL). The combined EtOAcextracts were washed with brine (2×300 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography (silica) and eluted with pet. ether/EtOAc (15:1) toafford methyl2-(2′-cyano-4′-methoxy-3′-propoxy-[1,1′-biphenyl]-3-yl)-3-(((trifluoromethyl)sulfonyl)oxy)acrylate(15.00 g, 74%). ¹H NMR (CDCl₃, 400 MHz): δ 7.56-7.59 (m, 1H), 7.48-7.52(m, 2H), 7.39-7.41 (m, 1H), 7.13-7.18 (m, 3H), 4.19 (t, J=6.8 Hz, 2H),3.93 (s, 3H), 3.91 (s, 3H), 1.83-1.92 (m, 2H), 1.09 (t, J=7.6 Hz, 3H).

Preparation 41: methyl2-(2′-cyano-4′-methoxy-3′-propoxy-[1,1′-biphenyl]-3-yl)-3-hydroxyacrylate

To a mixture of methyl2-(2′-cyano-4′-methoxy-3′-propoxy-[1,1′-biphenyl]-3-yl)acetate(Preparation 85, 12.0 g, 35.36 mmol) and ethyl formate (11.39 mL, 141.43mmol) in DCM (150 mL) was added TiCl₄ (13.41 g, 70.72 mmol, 7.62 mL) andEt₃N (8.59 g, 84.86 mmol, 11.76 mL) slowly at about 0° C. The mixturewas stirred at about 20° C. for about 1 h. Water (150 mL) was added andthe mixture was extracted with DCM (2×150 mL). The combined DCM extractswere washed with brine (150 mL), dried over Na₂SO₄ and concentrated toafford methyl2-(2′-cyano-4′-methoxy-3′-propoxy-[1,1′-biphenyl]-3-yl)-3-hydroxyacrylate(14.50 g), which was used directly without further purification. ¹H NMR(CDCl₃, 400 MHz): δ 12.09 (d, J=12.4 Hz, 1H), 7.43-7.44 (m, 3H),7.38-7.41 (m, 1H), 7.29-7.34 (m, 1H), 7.15 (s, 2H), 4.19 (t, J=6.8 Hz,2H), 3.92 (s, 3H), 3.85 (s, 3H), 1.84-1.93 (m, 2H), 1.07-1.11 (m, 3H).

Preparation 42:(R)-3-(1-((tert-butyldimethylsilyl)oxy)-3-iodopropan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine

A mixture of(R)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propylmethanesulfonate (Preparation 43, 45.5 g, 89.28 mmol) and lithium iodide(38.2 g, 286 mmol) in acetone (446 mL) was stirred at about 30° C. for 3days. The reaction was heated to about 50° C. for about 45 min. Themixture was cooled to about 20° C. and concentrated to remove acetone.The residue was diluted with DCM and washed with water (2×100 mL). TheDCM extract was dried over MgSO₄, filtered and concentrated. The residuewas triturated in heptanes/EtOAc (1:1, 100 mL) for about 45 min. Thesolid material was filtered and purified by column chromatography(silica) and eluted with heptanes/EtOAc (85:15 to 30:70) to afford(R)-3-(1-((tert-butyldimethylsilyl)oxy)-3-iodopropan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(41.2 g, 85%). ¹H NMR (CDCl₃, 400 MHz): δ 8.71 (d, J=2.3 Hz, 1H), 8.43(d, J=2.0 Hz, 1H), 7.71 (t, J=2.0 Hz, 1H), 7.09-7.15 (m, 2H), 6.98 (d,J=8.2 Hz, 1H), 4.06 (t, J=7.0 Hz, 2H), 3.98-4.02 (m, 1H), 3.93 (s, 3H),3.84-3.88 (m, 1H), 3.68-3.72 (m, 1H), 3.43-3.47 (m, 1H), 3.09-3.15 (m,1H), 1.87-1.96 (m, 2H), 1.08 (t, J=7.4 Hz, 3H), 0.89 (s, 9H), 0.05 (d,J=7.4 Hz, 6H). LCMS m/z=542 [MH]⁺.

Preparation 43:(R)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propylmethanesulfonate

To an ice cold solution of(S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propan-1-ol(Preparation 44, 42.8 g, 99.2 mmol) in DCM (600 mL) was added Et₃N (25.1mL, 178 mmol) and stirred for about 30 min. MsCl (9.98 mL, 129 mmol) wasadded dropwise and allowed to warm and stir at about 20° C. overnight.The mixture was washed with water, dried over MgSO₄, filtered, passedthrough a silica gel plug and concentrated to afford(R)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propylmethanesulfonate (45.5 g), which was used in Preparation 42. LCMSm/z=510 [MH]⁺.

Preparation 44:(S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propan-1-ol

To an ice cold solution of(S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propylacetate (Preparation 45, 45.7 g, 96.5 mmol) in THF (400 mL) was addedaqueous NaOH (154 mL, 1 N). The mixture was allowed to warm and stir atabout 20° C. for 2 days. The organic phase was separated andconcentrated. The residue was dissolved in DCM (300 mL). The aqueouslayer was extracted with DCM. The combined DCM extracts were washed withwater, brine, dried over Na₂SO₄, filtered and concentrated to afford(S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propan-1-ol(42.8 g), which was used in Preparation 43. LCMS m/z=432 [MH]⁺.

Preparation 45:(S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propylacetate

To an ice cold solution of(R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propylacetate (Preparation 46, 43.4 g, 121 mmol) in 2-MeTHF (1400 mL) wasadded DCM (800 mL), imidazole (41.1 g, 604 mmol) and TBS-Cl (91.0 g, 604mmol). The reaction mixture was warmed to about 20° C. and stirredovernight. The mixture was filtered and the solids washed with EtOAc.The combined filtrates were washed with water, brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography (silica) and eluted with heptanes/EtOAc (100:0 to 60:40)to afford(S)-3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propylacetate (48.3 g, 85%). ¹H NMR (CDCl₃, 400 MHz): δ 8.70 (d, J=2.0 Hz,1H), 8.45 (d, J=2.3 Hz, 1H), 7.74 (t, J=2.3 Hz, 1H), 7.08-7.14 (m, 2H),6.98 (d, J=8.2 Hz, 1H), 4.40-4.49 (m, 2H), 4.06 (t, J=7.0 Hz, 2H),3.86-3.95 (m, 5H), 3.17-3.23 (m, 1H), 2.04 (s, 3H), 1.67-1.96 (m, 2H),1.08 (t, J=7.4 Hz, 3H), 0.87 (s, 9H), 0.01 (d, J=2.3 Hz, 6H). LCMSm/z=474 [MH]⁺.

Preparation 46:(R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propylacetate

To a mixture of2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propane-1,3-diol(Preparation 82, 38.3 g, 121 mmol) in 2-MeTHF (1088 mL) was addedimmobilized Rhizomucor miehei lipase (1.53 g, Lipozyme® RM IM, NovozymesA/S, Denmark). The mixture was stirred at about 20° C. for about 5 min.Vinyl acetate (89.0 mL, 965 mmol) was added to the mixture followed by2-MeTHF (100 mL). The mixture was stirred at about 20° C. for about 39h. The mixture was filtered and the filter cake was washed with 2-MeTHF(50 mL). The combined filtrates were concentrated to afford(R)-3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propylacetate (36.0 g, 83%), which was used in Preparation 45.

Preparation 47a:3-(1,2-dibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine

To a mixture of3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine(Preparation 49, 8.00 g, 20.02 mmol) in DCM (150 mL) was addedpyridinium tribromide (CAS 39416-48-3, 7.68 g, 24.02 mmol) in oneportion at about 0° C. under N₂. The mixture was stirred at about 25° C.for about 3 h. The DCM mixture was washed with aqueous Na₂SO₃ (100 mL),brine (100 mL), dried over Na₂SO₄ and concentrated. The residue waspurified by column chromatography (silica) and eluted with pet.ether/EtOAc (10:1) to afford3-(1,2-dibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine(11.00 g) which was used directly for the next step. ¹H NMR (CDCl₃, 400MHz): δ 8.72-8.74 (m, 2H), 7.99 (t, J=2.0 Hz, 1H), 7.14 (dd, J=2.0, 8.4Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 4.37-4.40 (m,2H), 4.28 (d, J=11.2 Hz, 1H), 4.21-4.26 (m, 3H), 3.93 (s, 3H), 1.52 (t,J=7.2 Hz, 3H), 0.94 (s, 9H), 0.14 (d, J=9.6 Hz, 6H).

Preparation 47b:3-(1,2-dibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine

To a mixture of3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(Preparation 50, 7.00 g, 16.92 mmol) in DCM (150 mL) was addedpyridinium tribromide (CAS 39416-48-3, 6.49 g, 20.30 mmol) in oneportion at about 0° C. under N₂. The mixture was stirred at about 25° C.for about 3 h. The DCM mixture was washed with aqueous Na₂SO₃ (100 mL),brine (100 mL), dried over Na₂SO₄ and concentrated. The residue waspurified by column chromatography (silica) and eluted with pet.ether/EtOAc (10:1) to afford3-(1,2-dibromo-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(10.00 g), which was used directly for the next step. ¹H NMR (CDCl₃, 400MHz): δ 8.72-8.75 (m, 2H), 7.99 (t, J=2.0 Hz, 1H), 7.14 (dd, J=2.0, 8.0Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 4.39 (d, J=10.8Hz, 2H), 4.28 (d, J=10.8 Hz, 1H), 4.20 (d, J=10.4 Hz, 1H), 4.07 (t,J=6.8 Hz, 2H), 3.93 (s, 3H), 1.97-1.87 (m, 1H), 1.08 (t, J=7.2 Hz, 3H),0.93 (s, 9H), 0.14 (d, J=9.6 Hz, 6H).

Preparation 48:3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine

A mixture of3-(3,4-dimethoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(Preparation 91a, 2.0 g, 5.86 mmol),2-bromoallyloxy-tert-butyl-dimethyl-silane (Preparation 227, 1.47 g,5.86 mmol), Pd(dppf)Cl₂DCM (239.34 mg, 293 umol), Na₂CO₃ (621.26 mg,5.86 mmol) and KOAc (1.15 g, 11.72 mmol) in 1,4-dioxane (50 mL) andwater (5 mL) were heated to about 90° C. for about 12 h. The mixture wasfiltered and the filtrate concentrated. The residue was purified bycolumn chromatography (silica) and eluted with DCM/MeCN (5:1) to afford3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3,4-dimethoxyphenyl)pyridine(2.10 g, 5.45 mmol, 93%). ¹H NMR (CDCl₃, 400 MHz): δ 8.72 (d, J=2.0 Hz,1H), 8.61 (d, J=2.0 Hz, 1H), 7.85 (t, J=2.0 Hz, 1H), 7.14-7.16 (m, 1H),7.08 (d, J=2.0 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 5.52 (d, J=12.0 Hz, 2H),4.56 (s, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 0.93 (s, 9H), 0.12 (s, 6H).

Preparation 49:3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine

A mixture of 3-bromo-5-(3-ethoxy-4-methoxyphenyl)pyridine (Preparation92, 20 g, 64.9 mmol),tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane(Preparation 146, 23.23 g, 77.88 mmol), Pd(dppf)Cl₂ (1.42 g, 1.95 mmol),K₂CO₃ (17.94 g, 129.8 mmol) and KOAc (9.55 g, 97.35 mmol) in 1,4-dioxane(300 mL) and water (10 mL) was degassed and heated to about 90° C. forabout 16 h under N₂. The mixture was filtered and concentrated. Theresidue was purified by column chromatography (silica) and eluted withpet. ether/EtOAc (3:1) to afford3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine(18.0 g, 69%). ¹H NMR (CDCl₃, 400 MHz): δ 8.71 (d, J=2.0 Hz, 1H), 8.60(d, J=2.0 Hz, 1H), 7.84 (t, J=2.0 Hz, 1H), 7.14 (dd, J=2.0, 8.4 Hz, 1H),7.09 (d, J=2.4 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 5.54 (s, 1H), 5.50 (s,1H), 4.56 (s, 2H), 4.19 (q, J=7.2 Hz, 2H), 3.94 (s, 3H), 1.52 (t, J=7.2Hz, 3H), 0.93 (s, 9H), 0.12 (s, 6H).

Preparation 50:3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine

A mixture of 3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine (Preparation93a, 15.0 g, 46.55 mmol),tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane(Preparation 146, 18.05 g, 60.51 mmol), Pd(dppf)Cl₂ (1.70 g, 2.33 mmol),K₂CO₃ (12.87 g, 93.10 mmol) and KOAc (6.85 g, 69.83 mmol) in 1,4-dioxane(250 mL) and water (5 mL) was degassed and heated to about 90° C. forabout 16 h under N₂. The mixture was filtered and concentrated. Theresidue was purified by column chromatography (silica) and eluted withpet. ether/EtOAc (3:1) to afford3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(13.50 g, 70%). ¹H NMR (CDCl₃, 400 MHz): δ 8.71 (d, J=2.4 Hz, 1H), 8.60(d, J=2.0 Hz, 1H), 7.84 (t, J=2.0 Hz, 1H), 7.13 (dd, J=2.4, 8.4 Hz, 1H),7.10 (d, J=2.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 5.53 (d, J=1.2 Hz, 1H),5.50 (d, J=1.2 Hz, 1H), 4.56 (s, 2H), 4.06 (t, J=6.8 Hz, 2H), 3.93 (s,3H), 1.87-1.96 (m, 2H), 1.08 (t, J=7.2 Hz, 3H), 0.93 (s, 9H), 0.13 (s,6H).

Preparation 51:3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-isopropoxy-4-methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-isopropoxy-4-methoxyphenyl)pyridine(1.1 g, 75%) was prepared in an analogous manner to Preparation 50 using3-bromo-5-(3-isopropoxy-4-methoxyphenyl)pyridine (Preparation 94, 1.15g, 3.6 mmol) at about 90° C. for about 2 h. LCMS m/z=414 [MH]⁺.

Preparation 52:3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine(730 mg, 76%) was prepared in an analogous manner to Preparation 50using 3-bromo-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine (Preparation95, 0.75 g, 2.34 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 8.74 (d, J=2.0 Hz,1H), 8.61 (d, J=2.5 Hz, 1H), 7.85 (t, J=2.3 Hz, 1H), 7.47 (d, J=2.0 Hz,1H), 7.14-7.22 (m, 1H), 6.98 (d, J=8.5 Hz, 1H), 5.53 (dd, J=1.3, 10.3Hz, 2H), 4.50-4.62 (m, 2H), 3.92 (s, 3H), 3.84 (tt, J=3.2, 6.1 Hz, 1H),0.81-0.96 (m, 13H), 0.11-0.14 (m, 6H). LCMS m/z=412 [MH]⁺.

Preparation 53:3-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)pyridine

3-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)pyridine(6.7 g, 62%) was prepared in an analogous manner to Preparation 50 using3-bromo-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine(Preparation 96, 9.3 g, 21 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 8.71 (d,J=2.0 Hz, 1H), 8.60 (d, J=2.0 Hz, 1H), 7.83 (t, J=2.0 Hz, 1H), 7.13-7.18(m, 2H), 6.96-7.01 (m, 1H), 5.52 (dd, J=1.3, 10.3 Hz, 2H), 4.56 (s, 2H),4.16-4.22 (m, 2H), 4.02-4.07 (m, 2H), 3.92 (s, 3H), 0.92-0.95 (m, 9H),0.90 (s, 9H), 0.12 (s, 6H), 0.10 (s, 6H). LCMS m/z=530 [MH]⁺.

Preparation 54:3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine(12.9 g, 99%) was prepared in an analogous manner to Preparation 50using3-bromo-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine(Preparation 97, 10.8 g, 23.8 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 8.71 (d,J=2.5 Hz, 1H), 8.60 (d, J=2.0 Hz, 1H), 7.83 (t, J=2.2 Hz, 1H), 7.11-7.16(m, 2H), 6.98 (d, J=8.3 Hz, 1H), 5.49-5.54 (m, 2H), 4.56 (t, J=1.5 Hz,2H), 4.21 (t, J=6.4 Hz, 2H), 3.92 (s, 3H), 3.85 (t, J=5.9 Hz, 2H),2.05-2.13 (m, 2H), 0.92-0.94 (m, 9H), 0.89 (s, 9H), 0.12 (s, 6H), 0.05(s, 6H). LCMS m/z=544 [MH]⁺.

Preparation 55:3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine(1.6 g, 78%) was prepared in an analogous manner to Preparation 50 using3-bromo-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine (Preparation 98,1.4 g, 4.7 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 8.92 (d, J=2.5 Hz, 1H),8.70-8.73 (m, 1H), 7.73 (t, J=8.6 Hz, 1H), 6.84-6.90 (m, 1H), 6.07 (d,J=1.5 Hz, 1H), 5.76 (d, J=1.5 Hz, 1H), 4.76 (t, J=1.7 Hz, 2H), 4.06 (t,J=6.9 Hz, 2H), 3.94 (s, 3H), 1.81-1.86 (m, 2H), 1.03-1.09 (m, 3H), 0.95(s, 9H), 0.14 (s, 6H). LCMS m/z=433 [MH]⁺.

Preparation 56:3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(3-fluoropropoxy)-4-methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-(3-fluoropropoxy)-4-methoxyphenyl)pyridinewas prepared in an analogous manner to Preparation 50 using3-bromo-5-(3-(3-fluoropropoxy)-4-methoxyphenyl)pyridine (Preparation99).

Preparation 57:3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine

A solution of2-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)prop-2-en-1-ol(Preparation 76, 321 mg, 0.71 mmol) and imidazole (97.2 mg, 1.43 mmol)in DCM (20 mL) was added TBS-Cl (129 mg, 0.86 mmol) at about 0° C. Thereaction mixture was stirred at about 20° C. for about 15 h. AdditionalTBS-Cl (129 mg, 0.86 mmol) was added and the reaction mixture wasstirred at about 20° C. for about 20 h. The reaction mixture wasconcentrated and purified by column chromatography (silica) and elutedwith pet. ether/EtOAc (100:0 to 60:40) to afford3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine(361 mg, 75%). ¹H NMR (CDCl₃, 400 MHz): δ 8.66 (d, J=2.0 Hz, 1H), 8.51(d, J=2.0 Hz, 1H), 7.71 (t, J=2.3 Hz, 1H), 7.05-7.10 (m, 1H), 6.78-7.03(m, 2H), 5.51 (dd, J=1.5, 14.1 Hz, 2H), 4.55 (t, J=1.5 Hz, 2H), 4.17 (q,J=7.0 Hz, 2H), 3.93 (s, 3H), 1.43 (t, J=7.0 Hz, 3H), 0.88-0.94 (m, 9H),0.09-0.13 (m, 6H). LCMS m/z=450 [MH]⁺.

Preparation 58:3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridine

To a mixture of3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)pyridine(Preparation 86, 795 mg, 2.42 mmol),2-(3-ethoxy-5-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 132, 652 mg, 2.2 mmol), Pd(dppf)Cl₂-DCM and K₂CO₃ (760 mg,5.5 mmol) was suspended in 1,4-dioxane (20 mL) and water (0.7 mL). Themixture was degassed and heated to about 85° C. under N₂ for about 9 h.The mixture was concentrated and MTBE (50 mL) was added, stirring forabout 20 min. The mixture was filtered and the filtrate wasconcentrated. The residue was purified by column chromatography (silica)and eluted with pet. ether/EtOAc (100:0 to 80:20) to afford3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridine(660 mg, 72%). ¹H NMR (CDCl₃, 400 MHz): δ 8.66 (dd, J=2.2, 15.4 Hz, 2H),7.82 (t, J=2.0 Hz, 1H), 6.94 (dd, J=2.2, 11.0 Hz, 1H), 6.88 (t, J=1.7Hz, 1H), 5.50-5.57 (m, 2H), 4.54-4.57 (m, 2H), 4.18 (q, J=7.0 Hz, 2H),3.98 (s, 3H), 1.50 (t, J=7.1 Hz, 3H), 0.92 (s, 9H), 0.12 (s, 6H). LCMSm/z=418 [MH]⁺.

Preparation 59:3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridine(840 mg, 61%) was prepared in an analogous manner to Preparation 58using2-(3-chloro-5-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 133, 1.0 g, 3.2 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 8.66 (dd,J=2.2, 11.5 Hz, 2H), 7.83 (t, J=2.2 Hz, 1H), 7.19 (d, J=2.0 Hz, 1H),6.99 (d, J=2.0 Hz, 1H), 5.53 (dd, J=1.5, 12.2 Hz, 2H), 4.52-4.63 (m,2H), 4.17 (q, J=7.2 Hz, 2H), 3.94 (s, 3H), 1.51 (t, J=6.9 Hz, 3H),0.90-0.97 (m, 9H), 0.08-0.15 (m, 6H).

Preparation 60:3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)prop-1-en-2-fluoro-4-methoxyphenyl)pyridine(400 mg, 89%) was prepared in an analogous manner to Preparation 50using 3-bromo-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine (Preparation101, 350 mg, 1.07 mmol). ¹H NMR (CDCI₃ 400 MHz): δ 8.66 (t, J=1.7 Hz,1H), 7.84-7.86 (m, 1H), 6.91 (d, J=7.3 Hz, 1H), 6.75 (d, J=11.7 Hz, 1H),5.50-5.53 (m, 2H), 4.56 (t, J=1.3 Hz, 2H), 4.12 (q, J=7.0 Hz, 2H), 3.92(s, 3H), 1.48 (t, J=7.0 Hz, 3H), 0.92 (s, 9H), 0.11 (s, 6H. LCMS m/z=418[MH]*.

Preparation 61:3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-chloro-5-ethoxy-4-methoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridine(2.1 g, 48%) was prepared in an analogous manner to Preparation 58 using2-(2-chloro-5-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 135, 3.13 g, 10.0 mmol). LCMS m/z=434 [MH]⁺.

Preparation 62:3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine(5.0 g, 99%) was prepared in an analogous manner to Preparation 50 using3-bromo-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine (Preparation 102,7.0 g, 9.0 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 8.66 (s, 1H), 8.62 (d,J=2.0 Hz, 1H), 7.85 (d, J=1.5 Hz, 1H), 6.92 (d, J=7.3 Hz, 1H), 6.76 (d,J=11.7 Hz, 1H), 5.52 (d, J=9.8 Hz, 2H), 4.55 (s, 2H), 4.00 (t, J=6.8 Hz,2H), 3.91 (s, 3H), 1.84-1.93 (m, 2H), 1.06 (t, J=7.3 Hz, 3H), 0.94-0.92(m, 9H), 0.12-0.11 (m, 6H). LCMS m/z=432 [MH]⁺.

Preparation 63:3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridine(2.1 g, 62%) was prepared in an analogous manner to Preparation 58 using2-(4-(difluoromethoxy)-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 142, 2.46 g, 7.5 mmol). ¹H NMR (CDCl₃, 400 MHz): δ8.66-8.71 (m, 2H), 7.85 (d, J=2.1 Hz, 1H), 7.27-7.29 (m, 1H), 7.12-7.14(m, 2H) 6.63 (t, J=75.3 Hz, 1H), 5.53 (d, J=12.0 Hz, 2H), 4.56 (s, 2H),4.07 (t, J=6.4 Hz, 2H), 1.85-1.94 (m, 2H), 1.09 (t, J=7.4 Hz, 3H), 0.92(s, 9H), 0.12 (s, 6H). LCMS m/z=450 [MH]⁺.

Preparation 64:5′-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-3-fluoro-5-methoxy-6-propoxy-2,3′-bipyridine

To a mixture of 5′-chloro-3-fluoro-5-methoxy-6-propoxy-2,3′-bipyridine(Preparation 103, 3.0 g, 10.11 mmol) andtert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane(Preparation 146, 12.1 g, 40.4 mmol) in 1,4-dioxane (300 mL) was addedXphos Pd G2 (CAS 1310584-14-5, 0.64 g, 0.81 mmol), Pd(dppf)-tBu (0.66 g,1.01 mmol), K₂CO₃ (2.79 g, 20.2 mmol) and KOAc (0.50 g, 5.06 mmol). Themixture was degassed, heated to about 70° C. for about 16 h under N₂.The mixture was diluted with EtOAc (50 mL), dried over MgSO₄, filteredand concentrated. The residue was purified by column chromatography(silica) and eluted with pet. ether/EtOAc (100:0 to 85:15) to afford5′-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-3-fluoro-5-methoxy-6-propoxy-2,3′-bipyridine(3.1 g, 71%). ¹H NMR (CDCl₃, 400 MHz): δ 9.13-9.14 (m, 1H), 8.62 (d,J=2.1 Hz, 1H), 8.28 (t, J=2.1 Hz, 1H), 6.97 (d, J=11.4 Hz, 1H),5.51-5.54 (m, 2H), 4.57 (t, J=1.5 Hz, 2H), 4.44 (t, J=7.0 Hz, 2H), 3.93(s, 3H), 1.86-1.95 (m, 2H), 1.06 (t, J=7.5 Hz, 3H), 0.93 (s, 9H), 0.12(s, 6H). LCMS m/z=433 [MH]⁺.

Preparation 65:5′-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-6-methoxy-5-propoxy-3,3′-bipyridine

5′-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-6-methoxy-5-propoxy-3,3′-bipyridine(4.85 g, 87%) was prepared in an analogous manner to Preparation 58using2-methoxy-3-propoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(Preparation 124, 3.95 g, 13.5 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 8.67(dd, J=2.2, 16.9 Hz, 2H), 7.9 (d, J=2.2 Hz, 1H), 7.83 (t, J=2.2 Hz, 1H),7.23 (d, J=2.0 Hz, 1H), 5.47-5.60 (m, 2H), 4.56 (t, J=1.3 Hz, 2H),4.03-4.08 (m, 5H), 1.90-1.99 (m, 2H), 1.04-1.13 (m, 3H), 0.92 (s, 9H),0.10-0.13 (m, 6H).

Preparation 66:5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-2-methylpyridine

3-Bromo-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-methylpyridine(Preparation 87, 1.28 g, 3.7 mmol) and2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 113, 1.25 g, 4.49 mmol), Pd(dppf)Cl₂ (274 mg, 0.374 mmol)and K₂CO₃ (1.29 g, 9.35 mmol) was suspended in 1,4-dioxane (60 mL) andwater (2 mL). The mixture was degassed and heated to about 80° C. underN₂ for about 5 h. The mixture was concentrated and to the residue wasadded MTBE (100 mL), which was stirred for about 20 min. The mixture wasfiltered and the filter cake was washed with MTBE (50 mL). The combinedfiltrates were dried and concentrated. The residue was purified columnchromatography (silica) and eluted with pet. ether/EtOAc (100:0 to85:15) to afford5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-2-methylpyridine(640 mg, 41%). ¹H NMR (CDCl₃, 400 MHz): δ 8.54 (d, J=2.5 Hz, 1H), 7.54(d, J=2.0 Hz, 1H), 6.94-6.97 (m, 1H), 6.85-6.88 (m, 1H), 6.83-6.84 (m,1H), 5.48 (d, J=1.5 Hz, 1H), 5.43-5.45 (m, 1H), 4.52 (t, J=1.5 Hz, 2H),4.12 (q, J=7.0 Hz, 2H), 3.93 (s, 3H), 2.51 (s, 3H), 1.49 (t, J=7.0 Hz,3H), 0.90-0.93 (m, 9H), 0.09-0.11 (m, 6H). LCMS m/z=414 [MH]⁺.

Preparation 67:4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidine

Toa mixture of4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-chloro-6-(trifluoromethyl)pyrimidine(Preparation 90, 1.33 g, 3.77 mmol) in 1,4-dioxane (40 mL) was added2-(4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 114, 1.32 g, 4.52 mmol), K₃PO₄ (3.01 g, 11.3 mmol) andPd(dppf)Cl₂ (0.41 g, 0.57 mmol). The mixture was degassed and heated toabout 90° C. for about 5 h under N₂. The mixture was concentrated andthe residue was purified by column chromatography (silica) and elutedwith pet. ether:EtOAc (100:0 to 90:10) to afford4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidine(1.27 g, 70%). ¹H NMR (CDCl₃, 400 MHz): δ 8.13-8.16 (m, 1H), 8.07 (d,J=2.0 Hz, 1H), 7.61 (s, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.31 (d, J=1.1 Hz,1H), 5.95 (d, J=1.0 Hz, 1H), 4.65 (t, J=1.6 Hz, 2H), 4.13 (t, J=6.9 Hz,2H), 3.96 (s, 3H), 1.90-1.99 (m, 2H), 1.10 (t, J=7.5 Hz, 3H), 0.97 (s,9H), 0.13 (s, 6H). LCMS m/z=483 [MH]⁺.

Preparation 68:2-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-6-(3-ethoxy-4-methoxyphenyl)pyrazine

2-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-6-(3-ethoxy-4-methoxyphenyl)pyrazine(1.26 g, 65%) was prepared in an analogous manner to Preparation 50using 2-bromo-6-(3-ethoxy-4-methoxyphenyl)pyrazine (Preparation 104, 1.5g, 4.9 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 8.77-8.90 (m, 1H), 8.68 (s,1H), 7.69 (d, J=2.0 Hz, 1H), 7.60 (dd, J=2.1, 8.44 Hz, 1H), 6.99 (d,J=8.3 Hz, 1H), 6.07 (q, J=1.4 Hz, 1H), 5.77 (q, J=1.9 Hz, 1H), 4.80 (t,J=1.7 Hz, 2H), 4.23 (q, J=7.0 Hz, 2H), 3.96 (s, 3H), 1.53 (t, J=7.0 Hz,3H), 0.90-0.98 (m, 9H), 0.13-0.18 (m, 6H). LCMS m/z=401 [MH]⁺.

Preparation 69: ethyl2-(6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate

Ethyl2-(6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate(5.6 g, 82%) was prepared in an analogous manner to Preparation 50 usingethyl 2-(6-chloro-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate(Preparation 105, 5 g, 13.7 mmol). ¹H NMR (CD₃OD, 400 MHz): δ 8.05 (dd,J=2.1, 8.4 Hz, 1H), 8.01-8.03 (m, 1H), 7.46 (s, 1H), 7.05 (d, J=8.6 Hz,1H), 6.24 (d, J=1.2 Hz, 1H), 5.81 (d, J=1.5 Hz, 1H), 4.81 (t, J=1.6 Hz,2H), 4.21 (q, J=7.1 Hz, 2H), 4.05 (t, J=6.6 Hz, 2H), 3.91 (s, 3H), 3.88(s, 2H), 1.80-1.92 (m, 2H), 1.26-1.31 (m, 3H), 1.08 (t, J=7.5 Hz, 3H),0.95 (s, 9H), 0.13-0.16 (m, 6H). LCMS m/z=501 [MH]⁺.

Preparation 70:4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidine

4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidine(1 g, 77%) was prepared in an analogous manner to Preparation 58 using4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-chloropyrimidine(Preparation 89, 2.0 g, 5.2 mmol) and2-(4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 114, 0.817 g, 2.8 mmol) at about 90° C. and substitutingK₃PO₄ (1.55 g, 5.80 mmol) for K₂CO₃0.1H NMR (CDCl₃, 400 MHz): δ8.02-8.08 (m, 2H), 7.52 (s, 1H), 6.94-6.99 (m, 1H), 6.20 (d, J=1.5 Hz,1H), 5.84 (d, J=1.5 Hz, 1H), 4.80-4.86 (m, 4H), 4.09-4.15 (m, 2H),3.93-3.96 (m, 3H), 1.91-1.98 (m, 2H), 1.09 (t, J=7.5 Hz, 3H), 1.00 (s,9H), 0.97 (s, 9H), 0.17 (s, 6H), 0.15 (s, 6H). LCMS m/z=559 [MH]⁺.

Preparation 71:2-(4-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-6-(4-methoxy-3-propoxyphenyl)pyridine

2-(4-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-6-(4-methoxy-3-propoxyphenyl)pyridine(900 mg, 68%) was prepared in an analogous manner to Preparation 50using 2-bromo-6-(4-methoxy-3-propoxyphenyl)pyridine (Preparation 93b,1000 mg, 3.10 mmol) andtert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane(Preparation 148, 969 mg, 3.10 mmol). LCMS m/z=428 [MH]⁺.

Preparation 72:5-(3-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-3-(4-methoxy-3-propoxyphenyl)pyridazine

5-(3-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-3-(4-methoxy-3-propoxyphenyl)pyridazine(3.0 g, 89%) was prepared in an analogous manner to Preparation 50 using5-chloro-3-(4-methoxy-3-propoxyphenyl)pyridazine (Preparation 107, 2.2g, 7.9 mmol) andtert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-yl)oxy)silane(Preparation 147, 4.9 g, 15.8 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 9.14 (d,J=2.0 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.53 (dd,J=2.0, 8.3 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 5.58 (s, 1H), 5.53 (s, 1H),4.08-4.18 (m, 3H), 3.95 (s, 3H), 1.86-1.99 (m, 2H), 1.29 (d, J=6.9 Hz,3H), 1.08 (t, J=7.3 Hz, 3H), 0.93 (s, 9H), 0.12 (d, J=19.6 Hz, 6H). LCMSm/z=429 [MH]⁺.

Preparation 73:3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine

3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine(0.8 g, 77%) was prepared in an analogous manner to Preparation 50 using3-bromo-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine (Preparation 108,0.81 g, 3.28 mmol) andtert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane(Preparation 146, 0.98 g, 3.28 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 8.35(s, 1H), 8.26 (s, 1H), 6.95 (d, J=8.2 Hz, 1H), 6.83-6.86 (m, 1H), 6.78(d, J=2.0 Hz, 1H), 5.61-5.63 (m 1H), 5.10-5.12 (m, 1H), 4.31-4.32 (m,2H), 4.12 (q, J=7.0 Hz, 2H), 3.93 (s, 3H), 2.21 (s, 3H), 1.48 (t, J=7.0Hz, 3H), 0.91 (s, 9H), 0.08 (s, 6H). LCMS m/z=414 [MH]⁺.

Preparation 74:4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(3-ethoxy-4-methoxyphenyl)thiazole

4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-(3-ethoxy-4-methoxyphenyl)thiazolewas prepared (0.8 g, 91%) in an analogous manner to Preparation 50 using4-bromo-2-(3-ethoxy-4-methoxyphenyl)thiazole (Preparation 109, 0.68 g,2.16 mmol) andtert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane(Preparation 146, 0.84 g, 2.81 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 7.57(d, J=2.3 Hz, 1H), 7.58 (dd, J=2.3, 8.3 Hz, 1H), 7.17 (s, 1H), 6.91 (d,J=8.3 Hz, 1H), 6.07-6.08 (m, 1H), 5.50-5.52 (m, 1H), 4.60-4.61 (m, 1H),4.22 (q, J=7.0 Hz, 2H), 3.93 (s, 3H), 1.52 (t, J=7.0 Hz, 3H), 0.99 (s,1H), 0.95 (s, 9H), 0.13 (s, 6H). LCMS m/z=406 [MH]⁺.

Preparation 75:2-((tert-butyldimethylsilyl)oxy)-1-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)ethan-1-one

To a mixture of1-(6-bromopyridin-2-yl)-2-((tert-butyldimethylsilyl)oxy)ethan-1-one(Preparation 88, 1270 mg, 4.36 mmol), K₂CO₃ (1000 mg, 7.27 mmol), KOAc(357 mg, 3.63 mmol), Pd(dppf)Cl₂-DCM (151 mg, 0.182 mmol) and a solutionof 2-(4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 114, 1200 mg, 3.633 mmol) in 1,4-dioxane (24 mL) was addedwater (2.4 mL). The mixture was degassed and heated to about 90° C. forabout 16 h under N₂. The reaction was filtered through a pad of MgSO₄and silica gel, washing with DCM and EtOAc. The filtrate wasconcentrated and the residue was purified by column chromatography(silica) and eluted with heptane/EtOAc (100:0 to 95:5) to afford2-((tert-butyldimethylsilyl)oxy)-1-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)ethan-1-one(1.21 g, 80%). ¹H NMR (CDCl₃, 400 MHz): δ 7.84-7.93 (m, 3H), 7.72 (d,J=2.0 Hz, 1H), 7.58 (dd, J=2.0, 8.6 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H),5.42 (s, 2H), 4.12 (t, J=6.8 Hz, 2H), 3.95 (s, 3H), 1.90-2.00 (m, 2H),1.10 (t, J=7.4 Hz, 3H), 1.00 (s, 9H), 0.16-0.20 (m, 6H). LCMS m/z=416[MH]⁺.

Preparation 76:2-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)prop-2-en-1-ol

2-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)prop-2-en-1-ol(321mg, 61%) was prepared in an analogous manner to Preparation 50 using3-bromo-5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine(Preparation 100, 558 mg, 1.56 mmol) at about 100° C. for about 15 h. ¹HNMR (CDCl₃, 400 MHz): δ 8.70 (d, J=2.0 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H),7.76-7.79 (m, 1H), 7.07 (d, J=8.6 Hz, 1H), 7.01 (d, J=8.6 Hz, 1H), 6.96(t, J=54.4 Hz, 1H), 5.60 (s, 1H), 5.49 (s, 1H), 4.58 (s, 2H), 4.12-4.22(m, 2H), 3.93 (s, 3H), 1.75 (br s, 1H), 1.43 (t, J=7.0 Hz, 3H,). LCMSm/z=336 [MH]⁺.

Preparation 77:3-(5-(iodomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine

To a solution of(5-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan-5-yl)methylmethanesulfonate (Preparation 78, 140 mg, 0.30 mmol) in acetone (1.20mL) was added lithium iodide (201 mg, 1.50 mmol). The solution wasstirred at about 50° C. for about 16 h. The reaction was cooled to about50° C., diluted with EtOAc, washed with water, dried over Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography (silica) and eluted with heptane/EtOAc (100:0 to 0:100)to afford3-(5-(iodomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(138 mg, 92%). ¹H NMR (CDCl₃, 400 MHz): δ 8.74 (d, J=2.0 Hz, 1H), 8.45(d, J=2.3 Hz, 1H), 7.66 (t, J=2.0 Hz, 1H), 7.08-7.17 (m, 2H), 7.00 (d,J=8.2 Hz, 1H), 4.25-4.37 (m, 2H), 4.14-4.23 (m, 2H), 4.07 (t, J=6.8 Hz,2H), 3.93 (s, 3H), 3.81 (s, 2H), 1.92 (qd, J=7.2, 14.3 Hz, 2H), 1.49 (d,J=18.3 Hz, 6H), 1.08 (t, J=7.4 Hz, 3H). LCMS m/z=498 [MH]⁺.

Preparation 78:(5-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan-5-yl)methylmethanesulfonate

To a mixtureof(5-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan-5-yl)methanol(Preparation 79, 128 mg, 0.33 mmol) in DCM (7.0 mL) was added Me₃N (84μL, 0.60 mmol), followed by MsCl (33 μL, 0.43 mmol). The solution wasstirred at about 20° C. for about 3.5 h. The mixture was concentratedand the residue was purified by column chromatography (silica) andeluted with heptane/EtOAc (100:0 to 0:100) to afford(5-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan-5-yl)methylmethanesulfonate (144 mg, 94%). ¹H NMR (CDCl₃, 400 MHz): δ 8.75 (d,J=2.0 Hz, 1H), 8.47 (d, J=2.0 Hz, 1H), 7.72 (t, J=2.1 Hz, 1H), 7.08-7.17(m, 2H), 6.99 (d, J=8.2 Hz, 1H), 4.78 (s, 2H), 4.20-4.28 (m, 2H),4.03-4.18 (m, 4H), 3.93 (s, 3H), 2.92-3.01 (m, 3H), 1.87-1.96 (m, 2H),1.51 (d, J=4.3 Hz, 6H), 1.08 (t, J=7.4 Hz, 3H).

Preparation 79:(5-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan-5-yl)methanol

To a solution of2-(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propane-1,3-diol(Preparation 80, 406 mg, 1.17 mmol) in DCM (12 mL) was added2,2-dimethoxypropane (0.43 mL, 3.51 mmol) and pTSOH (33 mg, 0.18 mmol).The solution was stirred at about 40° C. for about 24 h and about 20° C.for about 4 days. The solution was concentrated and the residue waspurified by column chromatography (silica) and eluted with heptane/EtOAc(100:0 to 0:100 gradient) to afford(5-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2,2-dimethyl-1,3-dioxan-5-yl)methanol(129 mg, 28%). ¹H NMR (CDCl₃, 400 MHz): δ 8.71 (d, J=2.3 Hz, 1H), 8.50(d, J=2.0 Hz, 1H), 7.75 (t, J=2.1 Hz, 1H), 7.05-7.15 (m, 2H), 6.99 (d,J=8.6 Hz, 1H), 4.19 (d, J=5.5 Hz, 3H), 4.12-4.17 (m, 3H), 4.06 (t, J=6.8Hz, 2H), 3.93 (s, 3H), 1.91 (qd, J=7.2, 14.4 Hz, 2H), 1.62-1.64 (m, 1H),1.49 (d, J=5.1 Hz, 6H), 1.08 (t, J=7.4 Hz, 3H). LCMS m/z=388 [MH]⁺.

Preparation 80:2-(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propane-1,3-diol

To a solution of methyl3-hydroxy-2-(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propanoate(Preparation 81, 250 mg, 0.67 mmol) in methanol (2.0 mL) was added LiBH₄(17.5 mg, 0.80 mmol). The solution was stirred at about 20° C. for about21 h. The mixture was treated with saturated aqueous NH₄Cl and extractedwith DCM. The DCM extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated to afford2-(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propane-1,3-diol(55 mg, 24%). ¹H NMR (CDCl₃, 400 MHz): δ 8.49 (br s, 1H), 8.28 (br s,1H), 7.90 (br s, 1H), 6.83-7.00 (m, 2H), 6.77 (d, J=8.6 Hz, 1H), 4.78(br s, 2H), 4.04 (br s, 5H), 3.74-3.99 (m, 6H), 1.74-1.91 (m, 2H), 1.26(s, 1H), 1.00 (t, J=7.4 Hz, 3H). LCMS m/z=348 [MH]⁺.

Preparation 81: methyl3-hydroxy-2-(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propanoate

To a solution of methyl2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)acetate (Preparation 84, 65g, 210 mmol) in DMSO (200 mL) was added paraformaldehyde (6.81 g, 227mmol), followed by DMSO (300 mL). NaOMe (2.23 g, 41.2 mmol) was added,followed by another 100 mL of DMSO. The mixture was stirred at about 20°C. for about 18 h. The mixture was diluted with water (1200 mL) andextracted with diethyl ether and EtOAc. The diethyl ether and EtOAccombined extracts were washed with water, brine, dried over MgSO₄,filtered and concentrated. The residue was stirred with EtOH (200 mL) atabout 65° C. until the residue was dissolved. The solution was cooled toabout 20° C. with stirring for about 2 h. The mixture was cooled toabout 0° C. (ice water bath) for an additional 1 h. The mixture wasfiltered, and the filter cake was washed with ice-cold EtOH. Thecombined EtOH filtrates were concentrated and the residue purified bycolumn chromatography (silica) eluting with EtOAc/MeOH (95:5) to affordmethyl3-hydroxy-2-(hydroxymethyl)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propanoate(5.46 g, 7%). ¹H NMR (CDCl₃, 400 MHz): δ 8.64 (d, J=2.0 Hz, 1H), 8.40(d, J=2.0 Hz, 1H), 7.71 (t, J=2.0 Hz, 1H), 7.25 (s, 1H), 6.98-7.10 (m,2H), 6.94 (t, J=7.3 Hz, 1H), 4.36 (d, J=11.3 Hz, 2H), 4.24 (d, J=11.3Hz, 2H), 4.02 (t, J=6.6 Hz, 2H), 3.90 (s, 3H), 3.79 (s, 3H), 2.03 (s,1H), 1.78-1.97 (m, 2H), 1.05 (t, J=7.4 Hz, 3H).

Preparation 82:2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propane-1,3-diol

To an ice cold solution of methyl3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propanoate(Preparation 83, 26.4 g, 73.5 mmol) in MeOH (350 mL) was added LiBH₄(3.2 g, 147 mmol) in 3 portions. The mixture was stirred for about 1 h.The mixture was concentrated and diluted with DCM. The mixture waswashed with 2N NaOH. The DCM layer was separated, dried over Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography (silica) and eluted with DCM/MeOH (100:0 to 90:10) toafford 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propane-1,3-diol(20.3 g, 87%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.68 (d, J=2.3 Hz, 1H), 8.37(d, J=2.0 Hz, 1H), 7.84 (t, J=2.3 Hz, 1H), 7.21-7.25 (m, 2H), 7.06 (d,J=8.2 Hz, 1H), 4.64 (t, J=5.4 Hz, 2H), 4.03 (t, J=6.6 Hz, 2H), 3.81 (s,3H), 3.65-3.79 (m, 4H), 2.89-2.95 (m, 1H), 1.72-1.80 (m, 2H), 1.00 (t,J=7.4 Hz, 3H). LCMS m/z=318 [MH]⁺.

Preparation 83: methyl3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propanoate

A mixture of methyl 2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)acetate(Preparation 84, 30.0 g, 95 mmol), paraformaldehyde (3.14 g, 105 mmol)and NaOMe (1.03 g, 19.0 mmol) in anhydrous DMSO (317 mL) was stirred atabout 20° C. for about 16 h. The mixture was diluted with water (1200mL) and extracted with diethyl ether and EtOAc. The combined diethylether and EtOAc extracts were washed with water, brine, dried overMgSO₄, filtered and concentrated. The residue was dissolved in hot EtOH(120 mL). The solution was cooled to about 20° C. with stirring. Furthercooling, to about 0° C. (ice bath) affording a precipitate which wasfiltered to afford methyl3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propanoate (15.6g). The filtrate was concentrated and purified by column chromatography(silica) to provide additional solid (10.8 g). The solids were combinedto afford methyl3-hydroxy-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propanoate (26.4g, 78%). ¹H NMR (CDCl₃, 400 MHz): δ 8.72 (d, J=2.0 Hz, 1H), 8.45 (d,J=2.3 Hz, 1H), 7.76 (t, J=2.0 Hz, 1H), 7.07-7.12 (m, 2H), 6.97 (d, J=8.6Hz, 1H), 4.16-4.22 (m, 1H), 4.05 (t, J=7.0 Hz, 2H), 3.91-3.99 (m, 5H),3.76 (s, 3H), 2.66-2.70 (m, 1H), 1.67-1.95 (m, 2H), 1.08 (t, J=7.4 Hz,3H). LCMS m/z=346 [MH]⁺.

Preparation 84: methyl2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)acetate

A mixture of methyl 2-(5-bromopyridin-3-yl)acetate (55.5 g, 241.0 mmol),2-(4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 114, 84.7 g, 290 mmol) and anhydrous Na₂CO₃ (51.1 g, 482mmol) in 1,4-dioxane (700 mL) and water (180 mL) was degassed andstirred at about 20° C. for about 20 min under N₂. Pd(dppf)Cl₂ (9.85 g,12.1 mmol) was added to the mixture, which was heated to about 85° C.for about 18 h under N₂. The reaction was cooled to about 20° C. andconcentrated. The residue was partitioned between water and EtOAc. Theaqueous layer was extracted with EtOAc. The combined EtOAc extracts werewashed with water, brine, dried over Na₂SO₄, filtered and concentrated.The residue was purified by column chromatography (silica) eluting withheptane/EtOAc (85:15 to 40:60) to afford methyl2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)acetate (75.4 g, 88%). ¹HNMR (CDCl₃, 400 MHz): δ 8.72 (d, J=2.0 Hz, 1H), 8.46 (d, J=2.0 Hz, 1H),7.77 (t, J=2.0 Hz, 1H), 7.13 (dd, J=2.3, 8.6 Hz, 1H), 7.09 (d, J=2.3 Hz,1H), 6.98 (d, J=8.6 Hz, 1H), 4.06 (t, J=6.8 Hz, 2H), 3.92 (s, 3H), 3.70(s, 2H), 2.94 (s, 3H), 1.86-1.95 (m, 2H), 1.08 (t, J=7.4 Hz, 3H). LCMSm/z=316 [MH]⁺.

Preparation 85: methyl2-(2′-cyano-4′-methoxy-3′-propoxy-[1,1′-biphenyl]-3-yl)acetate

To a solution of 6-bromo-3-methoxy-2-propoxybenzonitrile (Preparation171, 10.0 g, 37.02 mmol), (3-(2-methoxy-2-oxoethyl)phenyl)boronic acid(7.18 g, 37.02 mmol), Pd(dppf)Cl₂ (1.35 g, 1.85 mmol), KOAc (3.63 g,37.02 mmol) and Na₂CO₃ (7.85 g, 74.04 mmol) in 1,4-dioxane (100 mL) andwater (5 mL) was degassed and heated to about 90° C. for about 5 h underN₂. The mixture was filtered and concentrated. The residue was purifiedby column chromatography (silica) and eluted with pet. ether/EtOAc (4:1)to afford methyl2-(2′-cyano-4′-methoxy-3′-propoxy-[1,1′-biphenyl]-3-yl)acetate (12.0 g,96%). ¹H NMR (CDCl₃, 400 MHz): δ 7.40-7.44 (m, 3H), 7.33 (d, J=6.8 Hz,1H), 7.15 (d, J=8.8 Hz, 2H), 4.18 (t, J=6.8 Hz, 2H), 3.92 (s, 3H), 3.71(d, J=5.6 Hz, 5H), 1.83-1.92 (m, 2H), 1.09 (t, J=7.2 Hz, 3H).

Preparation 86:3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)pyridine

A mixture oftert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane(Preparation 146, 14.9 g, 50 mmol), 3,5-dibromopyridine (12.4 g, 52.5mmol), Pd(dppf)Cl₂ (1.83 g, 2.5 mmol) and K₂CO₃ (20.7 g, 150 mmol) weresuspended in 1,4-dioxane (300 mL) and water (20 mL). The mixture wasdegassed and heated to about 85° C. for about 5 h under N₂. The mixturewas removed from heat and allowed to stand over the weekend. The mixturewas concentrated, MTBE (100 mL) was added and stirred for about 20 min.The mixture was filtered and the filter cake was washed with MTBE (50mL). The combined MTBE filtrates were dried and concentrated. Theresidue was purified by column chromatography (silica) eluting with pet.ether/EtOAc (100:0 to 95:5) to afford3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)pyridine (8.5g, 51.8%). ¹H NMR (CDCl₃, 400 MHz): δ 8.55-8.63 (m, 2H), 7.84-7.93 (m,1H), 5.44-5.55 (m, 2H), 4.49 (t, J=1.5 Hz, 2H), 0.91 (s, 9H), 0.10 (s,6H). LCMS m/z=329 [MH]⁺.

Preparation 87:3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-methylpyridine

A mixture oftert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane(Preparation 146, 4.2 g, 14.08 mmol), 3,5-dibromo-2-methylpyridine (3.71g, 14.8 mmol), Pd(dppf)Cl₂ (1030 mg, 1.41 mmol) and K₂CO₃ (5.84 g, 42.2mmol) were suspended in 1,4-dioxane (150 mL) and water (5 mL). Themixture was degassed and heated to about 80° C. for about 5 h under N₂.The mixture was concentrated and MTBE (100 mL) was added, stirring forabout 20 min. The mixture was filtered and the filter cake was washedwith MTBE (50 mL). The combined MTBE filtrates were concentrated and theresidue was purified by column chromatography (silica) eluting with pet.ether/EtOAc (100:0 to 95:5) to afford3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-methylpyridine(930 mg, 19.3%). ¹H NMR (CDCl₃, 400 MHz): δ 8.46-8.53 (m, 1H), 7.86 (d,J=2.0 Hz, 1H), 5.41-5.50 (m, 2H), 4.43-4.54 (m, 2H), 2.66 (s, 3H), 0.92(s, 9H), 0.10 (s, 6H).

Preparation 88:1-(6-bromopyridin-2-yl)-2-((tert-butyldimethylsilyl)oxy)ethan-1-one

A solution of 1-(6-bromopyridin-2-yl)-2-hydroxyethan-1-one (Preparation237, 977 mg, 4.52 mmol) and DCM (30 mL) cooled to about 0° C., was addedimidazole (770 mg, 11.3 mmol) and TBS-Cl (750 mg, 4.97 mmol). Themixture was stirred at about 0° C. for about 2.5 h. The reaction wasquenched with water and the layers were separated. The DCM layer waswashed with water and brine. The DCM layer was passed through through apad of MgSO₄ and silica gel. The filtrate was concentrated to afford1-(6-bromopyridin-2-yl)-2-((tert-butyldimethylsilyl)oxy)ethan-1-one(1.35 g, 90%). ¹H NMR (CDCl₃, 400 MHz): δ 7.93-8.04 (m, 1H), 7.62-7.78(m, 2H), 5.21 (s, 2H), 0.97 (s, 9H), 0.15 (s, 6H).

Preparation 89:4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-chloropyrimidine

4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-chloropyrimidine(0.9 g, 34%) was prepared in an analogous manner to Preparation 50 using4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dichloropyrimidine(Preparation 230, 1.65 g, 5.5 mmol) and K₃PO₄ as base. ¹H NMR (CDCl₃,400 MHz): δ 7.63 (s, 1H), 6.23 (d, J=1.5 Hz, 1H), 5.87 (d, J=1.5 Hz,1H), 4.76 (d, J=1.0 Hz, 2H), 4.62-4.66 (m, 2H), 0.97-0.99 (m, 9H), 0.94(s, 9H), 0.12-0.16 (m, 12H). LCMS m/z=429 [MH]⁺.

Preparation90:4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-chloro-6-(trifluoromethyl)pyrimidine

4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-2-chloro-6-(trifluoromethyl)pyrimidine(1.33 g, 66%) was prepared in an analogous manner to Preparation 50using 2,4-dichloro-6-(trifluoromethyl)pyrimidine (CAS 16097-64-6, 1.24g, 5.72 mmol) and substituting K₃PO₄ (4.57 g, 17.1 mmol) for K₂CO₃0.1HNMR (CDCl₃, 400 MHz): δ 7.77 (s, 1H), 6.38-6.39 (m, 1H), 5.99-6.00 (m,1H), 4.65 (t, J=1.5 Hz, 2H), 0.92-0.94 (m, 9H), 0.13 (s, 6H). LCMSm/z=353 [MH]⁺.

Preparation 91a:3-(3,4-dimethoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

A mixture of 3-bromo-5-(3,4-dimethoxyphenyl)pyridine (Preparation 91b,12.20 g, 41.48 mmol), Pin₂B₂ (21.07 g, 82.96 mmol), KOAc (8.14 g, 82.96mmol) and Pd(dppf)Cl₂ (607 mg, 830 umol) in 1,4-dioxane (500 mL) wasdegassed and stirred at about 110° C. for about 4 h under N₂. Themixture was concentrated and the residue was purified by columnchromatography (silica) eluting with pet. ether/EtOAc (100:1 to 10:1) toafford3-(3,4-dimethoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(6.00 g, 42%). ¹H NMR (CDCl₃, 400 MHz): δ 8.97 (d, J=2.3 Hz, 1H), 8.71(d, J=1.0 Hz, 1H), 8.14 (s, 1H), 7.27 (s, 1H), 7.22-7.26 (m, 1H), 7.06(d, J=8.3 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 1.33 (s, 13H).

Preparation 91b: 3-bromo-5-(3,4-dimethoxyphenyl)pyridine

A mixture of 3,5-dibromopyridine (17.90 g, 75.56 mmol),(3,4-dimethoxyphenyl) boronic acid (CAS 122775-35-3, 12.50 g, 68.69mmol), Na₂CO₃ (10.92 g, 103.0 mmol), KOAc (10.11 g, 103.03 mmol) andPd(dppf)Cl₂ (1.01 g, 1.37 mmol) in 1,4-dioxane (20 mL) was degassed andstirred at about 90° C. for about 8 h under N₂. The mixture was filteredand concentrated The residue was purified by column chromatography(silica) and eluted with pet. ether/EtOAc (20:1 to 1:1) to afford3-bromo-5-(3,4-dimethoxyphenyl)pyridine (20.2 g, 59%). ¹H NMR (DMSO-d₆,400 MHz): δ 8.88 (d, J=1.8 Hz, 1H), 8.61 (d, J=1.8 Hz, 1H), 8.35 (t,J=2.0 Hz, 1H), 7.28-7.35 (m, 2H), 7.05 (d, J=7.9 Hz, 1H), 3.85 (s, 3H),3.79 (s, 3H). LCMS m/z=294 [MH]⁺.

Preparation 92: 3-Bromo-5-(3-ethoxy-4-methoxyphenyl)pyridine

A mixture of2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 113, 20.0 g, 71.9 mmol), 3,5-dibromopyridine (34.07 g,143.8 mmol), K₂CO₃ (19.87 g, 143.8 mmol), KOAc (10.58 g, 107.9 mmol) andPd(dppf)Cl₂ (2.10 g, 2.88 mmol) in 1,4-dioxane (600 mL) and water (10mL) was degassed and heated to about 100° C. for about 5 h under N₂. Themixture was filtered and concentrated. The residue was purified bycolumn chromatography (silica) and eluted with pet. ether/EtOAc (5:1) toafford 3-bromo-5-(3-ethoxy-4-methoxyphenyl)pyridine (20 g, 90%). ¹H NMR(CDCl₃, 400 MHz): δ 8.71 (s, 1H), 8.60 (s, 1H), 7.96 (s, 1H), 7.11 (dd,J=2.0, 8.4 Hz, 1H), 7.05 (s, 1H), 6.97 (t, J=4.0 Hz, 1H), 4.18 (q, J=6.8Hz, 2H), 3.92 (s, 3H), 1.49 (t, J=6.8 Hz, 3H).

Preparation 93a: 3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine

2-(4-Methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 114, 28.00 g, 95.83 mmol), 3,5-dibromopyridine (45.40 g,191.66 mmol), K₂CO₃ (19.87 g, 143.75 mmol), KOAc (14.11 g, 143.75 mmol)and Pd(dppf)Cl₂ (3.51 g, 4.79 mmol) in 1,4-dioxane (600 mL) and water(10 mL) was degassed and heated to about 100° C. for about 5 h under N₂.The mixture was filtered and concentrated. The residue was purified bycolumn chromatography (silica) and eluted with pet. ether/EtOAc (5:1) toafford 3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine (15.00 g, 49%). ¹HNMR (CDCl₃, 400 MHz): δ 8.72 (d, J=2.0 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H),7.97 (t, J=2.0 Hz, 1H), 7.12 (dd, J=2.0, 8.4 Hz, 1H), 7.06 (d, J=2.4 Hz,1H), 6.98 (d, J=8.4 Hz, 1H), 4.06 (t, J=6.8 Hz, 2H), 3.93 (s, 3H),1.87-1.96 (m, 2H), 1.08 (t, J=7.2 Hz, 3H).

Preparation 93b: 2-bromo-6-(4-methoxy-3-propoxyphenyl)pyridine

2-(4-Methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 114, 10.6 g, 36.3 mmol), 2,6-dibromopyridine (9.0 g, 38.0mmol), K₃PO₄ (16.1 g, 76.0 mmol) and Pd(dppf)Cl₂ (1.55 g, 1.90 mmol) indioxane (6 mL) and water (1.5 mL) was degassed and heated to about 80°C. overnight. The mixture was diluted with brine (150 mL) and EtOAc (150mL). The layers were separated and the EtOAc layer was washed with brine(75 mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography (silica) and eluted with heptane/EtOAc(100:0 to 3:1) to afford 2-bromo-6-(4-methoxy-3-propoxyphenyl)pyridine(5.34 g, 44%). ¹H NMR (CDCl₃, 400 MHz): δ 7.81-8.72 (m, 2H), 7.51-7.57(m, 2H), 7.35 (d, J=7.4 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 4.11 (t, J=6.6Hz, 2H), 3.93 (s, 3H), 1.86-1.97 (m, 2H), 1.09 (t, J=7.4 Hz, 3H).

Preparation 94: 3-bromo-5-(3-isopropoxy-4-methoxyphenyl)pyridine

3-bromo-5-(3-isopropoxy-4-methoxyphenyl)pyridine (1.15 g, 52%) wasprepared in an analogous manner to Preparation 93a using2-(3-isopropoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 115, 2 g, 6.8 mmol) at about 120° C. for about 2 h. ¹H NMR(CDCl₃, 400 MHz): δ8.71 (d, J=1.5 Hz, 1H), 8.61 (d, J=2.5 Hz, 1H),7.95-7.98 (m, 1H), 7.12-7.16 (m, 1H), 7.09 (d, J=2.5 Hz, 1H), 6.99 (d,J=8.5 Hz, 1H), 4.58-4.67 (m, 1H), 3.92 (s, 3H), 1.42 (d, J=6.0 Hz, 6H).LCMS m/z=323 [MH]⁺.

Preparation 95: 3-bromo-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine

3-bromo-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine (860 mg, 52%) wasprepared in an analogous manner to Preparation 93a using2-(3-cyclopropoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 117, 1.5 g, 5.2 mmol) at about 120° C. for about 2 h. ¹HNMR (CDCl₃, 400 MHz): δ 8.74 (d, J=2.0 Hz, 1H), 8.62 (d, J=2.5 Hz, 1H),7.99 (t, J=2.2 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.14 (dd, J=2.5, 8.3 Hz,1H), 6.97 (d, J=8.3 Hz, 1H), 3.92 (s, 3H), 3.81-3.87 (m, 1H), 0.83-0.96(m, 4H). LCMS m/z=321 [MH]⁺.

Preparation 96:3-bromo-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine3-bromo-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine

3-bromo-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine3-bromo-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine(6.8 g, 32%) was prepared in an analogous manner to Preparation 93ausingtert-butyl(2-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethoxy)dimethylsilane(Preparation 120, 20 g, 49 mmol) at about 120° C. for about 3 h. ¹H NMR(CDCl₃, 400 MHz): δ 8.69-8.78 (m, 1H), 8.61 (d, J=2.2 Hz, 1H), 7.97 (t,J=2.1 Hz, 1H), 7.13 (qd, J=2.2, 4.4 Hz, 2H), 6.98 (d, J=8.8 Hz, 1H),4.16-4.23 (m, 2H), 4.02-4.09 (m, 2H), 3.92 (s, 3H), 0.88-0.93 (m, 9H),0.10 (s, 6H). LCMS m/z=439 [MH]⁺.

Preparation 97:3-bromo-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine

3-bromo-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine(12.4 g, 64%) was prepared in an analogous manner to Preparation 93ausingtert-butyl(3-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propoxy)dimethylsilane(Preparation 121, 18 g, 42.6 mmol). ¹H NMR (CDCl₃, 400 MHz): 58.68 (d,J=2.0 Hz, 1H), 8.58 (d, J=2.5 Hz, 1H), 7.94-8.01 (m, 1H), 7.10 (dd,J=2.5, 8.3 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 4.19(t, J=6.4 Hz, 2H), 3.90 (s, 3H), 3.80-3.86 (m, 2H), 2.03-2.11 (m, 2H),0.85-0.90 (m, 9H), 0.04 (s, 6H). LCMS m/z=454 [MH]⁺.

Preparation 98: 3-bromo-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine

3-Bromo-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine (1.8 g, 74%) wasprepared in an analogous manner to Preparation 93a using2-(3-(2-fluoroethoxy)-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 122, 2.2 g, 7.4 mmol) at about 120° C. for about 2 h. ¹HNMR (CDCl₃, 400 MHz): δ 8.68-8.76 (m, 1H), 8.58-8.65 (m, 1H), 7.97 (t,J=2.3 Hz, 1H), 7.18 (dd, J=2.0, 8.5 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H),7.00 (d, J=8.5 Hz, 1H), 4.83-4.92 (m, 1H), 4.72-4.81 (m, 1H), 4.37-4.44(m, 1H), 4.25-4.36 (m, 1H), 3.88-3.97 (m, 3H). LCMS m/z=325 [MH]⁺.

Preparation 99: 3-bromo-5-(3-(3-fluoropropoxy)-4-methoxyphenyl)pyridine

3-Bromo-5-(3-(3-fluoropropoxy)-4-methoxyphenyl)pyridine was prepared inan analogous manner to Preparation 93a using2-(3-(3-fluoropropoxy)-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 123).

Preparation 100:3-bromo-5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine

3-Bromo-5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine(1000 mg,28%) was prepared in an analogous manner to Preparation 93a using2-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 127, 4.09 g, 12.46 mmol) heated to about 100° C. for about15 h. ¹H NMR (400 MHz, CDCl₃): δ 8.67 (d, J=2.0 Hz, 1H), 8.52 (d, J=1.5Hz, 1H), 7.86 (t, J=2.0 Hz, 1H), 6.84-7.13 (m, 4H), 4.17 (q, J=7.4 Hz,2H), 3.93 (s, 3H), 1.42 (t, J=7.0 Hz, 3H). LCMS m/z=359 [MH]⁺.

Preparation 101:3-bromo-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine

3-Bromo-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine (350 mg, 27%) wasprepared as in an analogous manner to Preparation 93a using2-(5-ethoxy-2-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 134, 1.2 g, 4.05 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 8.68 (t,J=1.7 Hz, 1H), 8.63 (d, J=2.1 Hz, 1H), 7.98-8.00 (m, 1H), 6.88 (d, J=7.3Hz, 1H), 6.75 (d, J=11.7 Hz, 1H), 4.12 (q, J=7.0 Hz, 2H), 3.92 (s, 3H),1.49 (t, J=7.0 Hz, 3H). LCMS m/z=327 [MH]⁺.

Preparation 102: 3-bromo-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine

3-Bromo-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine (3.4 g, 31%) wasprepared as in an analogous manner to Preparation 93a using2-(2-fluoro-4-methoxy-5-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 138, 10 g, 32 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 8.68 (t,J=1.5 Hz, 1H), 8.63 (d, J=2.4 Hz, 1H), 7.99 (q, J=2.0 Hz, 1H), 6.88 (d,J=7.8 Hz, 1H), 6.75 (d, J=11.7 Hz, 1H), 4.00 (t, J=6.8 Hz, 2H), 3.91 (s,3H), 1.84-1.93 (m, 2H), 1.06 (t, J=7.6 Hz, 3H). LCMS m/z=339 [MH]⁺.

Preparation 103: 5′-chloro-3-fluoro-5-methoxy-6-propoxy-2,3′-bipyridine

5′-Chloro-3-fluoro-5-methoxy-6-propoxy-2,3′-bipyridine (3.11 g, 78%) wasprepared in an analogous manner to Preparation 93a using3-fluoro-2-iodo-5-methoxy-6-propoxypyridine (Preparation 220, 4.18 g,13.44 mmol) and (5-chloropyridin-3-yl)boronic acid (2.11 g, 13.4 mmol)at about 90° C. for about 16 h. ¹H NMR (CDCl₃, 400 MHz): δ 9.13 (s, 1H),8.53 (d, J=2.5 Hz, 1H), 8.27 (t, J=2.1 Hz, 1H), 6.97 (d, J=11.5 Hz, 1H),4.43 (t, J=6.9 Hz, 2H), 3.93 (s, 3H), 1.86-1.95 (m, 2H), 1.07 (t, J=7.5Hz, 3H). LCMS m/z=328 [MH]⁺.

Preparation 104: 2-bromo-6-(3-ethoxy-4-methoxyphenyl)pyrazine

2-Bromo-6-(3-ethoxy-4-methoxyphenyl)pyrazine (2.9 g, 52%) was preparedin an analogous manner to Preparation 93a using2-(3-ethoxy-2-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 113, 5 g, 18 mmol) and 2,6-dibromopyrazine (6.4 g, 27 mmol)at about 110° C. for about 16 h. ¹H NMR (CDCl₃, 400 MHz): δ 8.86-8.92(m, 1H), 8.53 (s, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.57 (dd, J=2.2, 8.3 Hz,1H), 6.98 (d, J=8.3 Hz, 1H), 4.23 (q, J=6.9 Hz, 2H), 3.95 (s, 3H), 1.53(t, J=7.0 Hz, 3H). LCMS m/z=309 [MH]⁺.

Preparation 105: ethyl2-(6-chloro-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate

POCl₃ (253 mL, 2716 mmol) was added to ethyl2-(2-(4-methoxy-3-propoxyphenyl)-6-oxo-1,6-dihydropyrimidin-4-yl)acetate(Preparation 106, 42.98 g, 124.08 mmol), followed by pyridinehydrochloride (14.3 g, 124 mmol) at about 25° C. The resulting mixturewas heated to about 80° C. for about 0.5 h. The mixture was diluted withEtOAc (200 mL) and added into water dropwise. The EtOAc layer wastreated with NaHCO₃. The EtOAc layer was washed with brine, dried withNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography on a reversed-phase column eluting with MeCN/water (0:100to 100:0) to afford ethyl2-(6-chloro-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate (22.07g, 49%). ¹H NMR (CDCl₃, 400 MHz): δ 8.08 (dd, J=2.1, 8.4 Hz, 1H), 7.98(d, J=2.0 Hz, 1H), 7.20 (s, 1H), 6.95 (d, J=8.6 Hz, 1H), 4.24 (q, J=7.2Hz, 2H), 4.11 (t, J=6.9 Hz, 2H), 3.95 (s, 3H), 3.85 (s, 2H), 1.89-1.96(m, 2H), 1.31 (t, J=7.2 Hz, 3H), 1.09 (t, J=7.5 Hz, 3H). LCMS m/z=365[MH]⁺.

Preparation 106: ethyl2-(2-(4-methoxy-3-propoxyphenyl)-6-oxo-1,6-dihydropyrimidin-4-yl)acetate

A mixture of 4-methoxy-3-propoxybenzimidamide (Preparation 233, 25.3 g,121 mmol), NaHCO₃ (12.2 mg, 146 mmol) and diethyl1,3-acetonedicarboxylate (CAS 105-50-0, 29.4 g, 146 mmol) in EtOH (500mL) was stirred at about 100° C. for about 24 h. The mixture wasfiltered, and the filter cake was washed with MTBE (200 mL), MeOH (100mL) and DCM (50 mL) to afford ethyl2-(2-(4-methoxy-3-propoxyphenyl)-6-oxo-1,6-dihydropyrimidin-4-yl)acetate(34.34 g, 82%). ¹H NMR (CDCl₃, 400 MHz): δ 12.44 (br s, 1H), 7.73-7.86(m, 2H), 6.99 (d, J=8.3 Hz, 1H), 6.33 (s, 1H), 4.23 (q, J=7.3 Hz, 2H),4.16 (t, J=6.9 Hz, 2H), 3.96 (s, 3H), 3.66 (s, 2H), 1.92-1.97 (m, 2H),1.30 (t, J=7.2 Hz, 3H), 1.10 (t, J=7.5 Hz, 3H). LCMS m/z=346 [MH]⁺.

Preparation 107: 5-chloro-3-(4-methoxy-3-propoxyphenyl)pyridazine

5-chloro-3-(4-methoxy-3-propoxyphenyl)pyridazine (2.9 g, 52%) wasprepared in an analogous manner to Preparation 93a using2-(4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 114, 4.3 g, 14.7 mmol) and 3,5-dichloropyridazine (2.3 g,15.5 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 9.08 (d, J=2.5 Hz, 1H), 7.84 (d,J=2.5 Hz, 2H), 7.51 (dd, J=2.2, 8.6 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H),4.12 (t, J=6.9 Hz, 2H), 3.95 (s, 3H), 1.92-1.97 (m, 2H), 1.08 (t, J=7.3Hz, 3H). LCMS m/z=278 [MH]⁺.

Preparation 108: 3-bromo-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine

3-bromo-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine (0.82 g, 35%) wasprepared in an analogous manner to Preparation 93a using2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 113, 2.0 g, 7.19 mmol) and 3,5-dibromo-4-methylpyridine(2.71 g, 10.8 mmol) at about 120° C. for about 2 h. ¹H NMR (CDCl₃, 400MHz): δ 8.61 (s, 1H), 8.32 (s, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.81-6.83(m, 1H), 6.78 (d, J=2.3 Hz, 1H), 4.10 (q, J=7.0 Hz, 2H), 3.92 (s, 3H),2.34 (s, 3H), 1.47 (t, J=7.0 Hz, 3H). LCMS m/z=323 [MH]⁺.

Preparation 109: 4-bromo-2-(3-ethoxy-4-methoxyphenyl)thiazole

To a mixture of Pd(OAc)₂ (CAS 3375-31-3, 40.4 mg, 0.18 mmol) andXantphos (CAS 161265-03-8, 208.0 mg, 0.36 mmol), stirring for about 10min., was added2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 113, 1.0 g, 3.60 mmol), 2,4-dibromothiazole (0.83 g, 3.42mmol) and K₃PO₄ (2.44 g, 11.5 mmol). The combined mixture was degassedand heated to about 60° C. for about 16 h. The mixture was concentratedand the residue was purified by column chromatography (silica) elutingwith pet. ether:EtOAc (100:0 to 85:15) to afford4-bromo-2-(3-ethoxy-4-methoxyphenyl)thiazole (0.68 g, 60%). ¹H NMR(CDCl₃, 400 MHz): δ 7.51 (d, J=2.3 Hz, 1H), 7.45 (dd, J=2.3, 8.3 Hz,1H), 7.14 (s, 1H), 6.90 (d, J=8.3 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 3.93(s, 3H), 1.51 (t, J=7.0 Hz, 3H). LCMS m/z=315 [MH]⁺.

Preparation 110: ethyl2-(6-bromopyridin-2-yl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propanoate

To a mixture of sodium iodide (1.05 g, 6.98 mmol) and acetone (1.50 mL)was added 2-(chloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (187mg, 1.06 mmol) and was stirred at about 20° C. for about 30 min. Themixture was filtered through a pad of Celite® and the filtrateconcentrated. The residue was dissolved and concentrated with anhydrousTHF (3×5 mL). The residue was dissolved in THF (6.0 mL) and added to acold suspension of NaH (60% dispersion in mineral oil, 349 mg, 8.73mmol) and ethyl 2-(6-bromopyridin-2-yl)propanoate (Preparation 111,1.502 g, 5.819 mmol) in THF (13.0 mL), which had been degassed under N₂.The combined mixture was stirred at about 20° C. for about 18 h. Themixture was treated with saturated aqueous NH₄Cl and extracted withEtOAc. The combined EtOAc extracts were washed with brine, dried overNa₂SO₄, filtered and concentrated. The residue was dissolved in DMSO (5mL) and was purified by preparative HPLC (Biotage C18 RP column, 60 g)eluting with MeCN (0.1% NH₄CO₂H)/water (0:100 to 100:0) to afford ethyl2-(6-bromopyridin-2-yl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propanoate(339 mg, 14%). ¹H NMR (CDCl₃, 500 MHz): δ 7.44-7.48 (m, 1H), 7.31 (m,1H), 7.25-7.29 (m, 2H), 4.15 (q, J=7.1 Hz, 2H), 1.67-1.70 (m, 3H), 1.54(s, 2H), 1.23-1.25 (m, 7H), 1.20 (d, J=3.9 Hz, 13H). LCMS m/z=399 [MH]⁺.

Preparation 111: ethyl 2-(6-bromopyridin-2-yl)propanoate

To a solution of ethyl 2-(6-bromopyridin-2-yl)acetate (Preparation 112,5.72 g, 23.4 mmol) in THF (117 mL) cooled to about −78° C. was added asolution of LiHMDS in THF (1.0 M, 29.3 mL, 29.3 mmol). The solution wasstirred for about 1 h and iodomethane (3.33 g, 23.4 mmol, 1.46 mL) wasadded dropwise. The reaction was allowed to warm to about 20° C. overabout 19 h. The reaction mixture was diluted with EtOAc. The mixture waswashed with saturated aqueous NH₄Cl, brine, dried over MgSO₄ and Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography (silica) and eluted with heptanes/EtOAc (100:0 to 80:20)to afford ethyl 2-(6-bromopyridin-2-yl)acetate (5.06 g, 84%). ¹H NMR(CDCl₃, 400 MHz,): δ 7.50-7.57 (m, 1H), 7.39 (d, J=7.8 Hz, 1H),7.26-7.31 (m, 1H), 4.19 (q, J=7.0 Hz, 2H), 3.93 (q, J=7.0 Hz, 1H), 1.57(d, J=7.4 Hz, 3H), 1.25 (t, J=7.0 Hz, 3H). LCMS m/z=259 [MH]⁺.

Preparation 112: ethyl 2-(6-bromopyridin-2-yl)acetate

To a solution of 2-bromo-6-methylpyridine (CAS 5315-25-3, 10.2 g, 59.1mmol) in THF (62 mL) was cooled to about −78° C. under N₂ was added asolution of LDA in THF (2.0 M, 59 mL, 118 mmol) slowly while stirring.The solution was stirred at about −78° C. for about 30 min. To themixture was added diethyl carbonate (8.6 mL, 70.9 mmol) at about −78° C.The mixture was allowed to warm to about 20° C. over overnight. Thereaction was cooled to about 0° C. and diluted with saturated aqueousNH₄Cl solution. The aqueous layer was extracted with DCM and thecombined DCM extracts were washed with water, brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography (silica) and eluted with heptanes/EtOAc (100:0 to 60:40)to afford ethyl 2-(6-bromopyridin-2-yl)acetate (7.7 g, 53%). ¹H NMR(CDCl₃, 400 MHz,): δ 7.55 (t, J=7.8 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H),7.28-7.34 (m, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.85 (s, 2H), 1.26-1.34 (m,3H). LCMS m/z=245 [MH]⁺.

Preparation 113:2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 4-bromo-2-ethoxy-1-methoxybenzene (Preparation 150, 48.0 g,207.7 mmol), Pd(dppf)Cl₂ (4.56 g, 6.23 mmol), Pin₂B₂ (58.0 g, 228.5mmol) and KOAc (40.8 g, 415.4 mmol) in 1,4-dioxane (500 mL) was degassedand heated to about 90° C. for about 16 h under N₂. The mixture wasfiltered and concentrated. The residue was purified by columnchromatography (silica) and eluted with pet. Ether/EtOAc (10:1) toafford2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(50.0 g, 86%). ¹H NMR (CDCl₃, 400 MHz): δ 7.41 (d, J=8.0 Hz, 1H), 7.30(s, 1H), 6.89 (d, J=8.0 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.90 (s, 3H),1.47 (t, J=7.2 Hz, 3H), 1.34 (s, 12H).

Preparation 114:2-(4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 4-bromo-1-methoxy-2-propoxybenzene (Preparation 151, 43.00g, 175.43 mmol), KOAc (34.43 g, 350.86 mmol), Pin₂B₂ (49.00 g, 192.97mmol) and Pd(dppf)Cl₂-DCM (4.30 g, 5.26 mmol) in 1,4-dioxane (500 mL)was degassed and stirred at about 80° C. for about 16 h. The solid wasremoved by filtration and the filtrate was concentrated. The residue waspurified by column chromatography (silica) and eluted with pet.Ether/EtOAc (10:1) to afford2-(4-methoxy-3-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(51.0 g, 99%). ¹H NMR (CDCl₃, 400 MHz): δ 7.40-7.42 (m, 1H), 7.30 (d,J=1.2 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 4.03 (t, J=7.0 Hz, 2H), 3.89 (s,3H), 1.84-1.93 (m, 2H), 1.34 (s, 12H), 1.05 (t, J=7.4 Hz, 3H).

The following compounds were prepared using the appropriate bromide and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane), followingthe procedure described in Preparation 114.

Preparation No. Structure/Name Source Analytical Data 115

Preparation 152 ¹H NMR (CDCl₃, 400 MHz): δ 7.40-7.44 (m, 1H), 7.33 (d, J= 1.5 Hz, 1H), 6.87-6.91 (m, 1H), 4.62 (td, J = 6.1, 12.2 Hz, 1H), 3.88(s, 3H), 1.36-1.39 (m, 6H), 1.34 (s, 12H). LCMS m/z = 293 [MH]⁺. 116

Preparation 153 ¹H NMR (CDCl₃, 400 MHz): δ 7.41 (dd, J = 1.2, 8.1 Hz,1H), 7.29 (d, J = 1.0 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 3.89 (s, 3H),3.82 (d, J = 6.9 Hz, 2H), 2.16-2.23 (m, 1H), 1.33- 1.37 (m, 12H), 1.05(d, J = 6.4 Hz, 6H). LCMS m/z = 307 [MH]⁺. 117

Preparation 154 ¹H NMR (CDCl₃, 400 MHz): δ 7.62 (d, J = 1.0 Hz, 1H),7.40-7.48 (m, 1H), 6.83-6.91 (m, 1H), 3.87 (s, 3H), 3.81-3.86 (m, 1H),1.33-1.36 (m, 12H), 0.80-0.88 (m, 4H). LCMS m/z = 291 [MH]⁺. 118

Preparation 155 ¹H NMR (CDCl₃, 400 MHz): δ 7.43-7.51 (m, 1H), 7.37 (d, J= 1.5 Hz, 1H), 6.88-6.92 (m, 1H), 5.135.15 (m, 1H), 3.87 (s, 3H),3.09-3.18 (m, 3H), 2.89-2.96 (m, 1H), 2.39- 2.47 (m, 1H), 2.04-2.07 (m,1H), 1.34 (s, 12H). LCMS m/z = 337 [MH]⁺. 119

Preparation 156 ¹H NMR (CDCl₃, 400 MHz): δ 7.41-7.48 (m, 1H), 7.32 (d, J= 1.5 Hz, 1H), 6.86-6.93 (m, 1H), 4.26- 4.37 (m, 1H), 3.86 (s, 3H),2.87-3.01 (m, 2H), 2.51- 2.62 (m, 2H), 2.13-2.25 (m, 2H), 1.98-2.10 (m,2H), 1.29-1.36 (m, 12H). 120

Preparation 157 ¹H NMR (CDCl₃, 400 MHz): δ 7.42 (dd, J = 1.5, 7.8 Hz,1H), 7.34 (d, J = 1.5 Hz, 1H), 6.86-6.90 (m, 1H), 4.10-4.18 (m, 2H),3.99-4.03 (m, 2H), 3.88 (s, 3H), 1.34 (s, 12H), 0.90- 0.92 (m, 9H),0.09-0.11 (m, 6H). LCMS m/z = 409 [MH]⁺. 121

Preparation 158 ¹H NMR (CDCl₃, 400 MHz): δ 7.40-7.43 (m, 1H), 7.33 (d, J= 1.5 Hz, 1H), 6.86-6.89 (m, 1H), 4.18 (t, J = 6.6 Hz, 2H), 3.88 (s,3H), 3.81-3.85 (m, 2H), 2.05-2.09 (m, 2H), 1.34 (s, 12H), 0.90 (s, 9H),0.05- 0.06 (m, 6H). LCMS m/z = 423 [MH]⁺. 122

Preparation 159 ¹H NMR (CDCl₃, 400 MHz): δ 7.46 (dd, J = 1.5, 7.8 Hz,1H), 7.32 (d, J = 1.0 Hz, 1H), 6.89-6.93 (m, 1H), 4.83-4.88 (m, 1H),4.72-4.75 (m, 1H), 4.34- 4.38 (m, 1H), 4.27-4.31 (m, 1H), 3.90 (s, 3H),1.34 (s, 12H). LCMS m/z = 297 [MH]⁺. 123

Preparation 160 ¹H NMR (CDCl₃, 400 MHz): δ 7.44 (dd, J = 1.5, 7.8 Hz,1H), 7.33 (d, J = 1.5 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 4.74 (t, J =5.9 Hz, 1H), 4.62 (t, J = 5.9 Hz, 1H), 4.20 (t, J = 6.4 Hz, 2H), 3.89(s, 3H), 2.27-2.30 (m, 1H), 2.20- 2.23 (m, 1H), 1.32-1.37 (m, 12H). LCMSm/z = 311 [MH]⁺. 124

Preparation 215 ¹H NMR (CDCl₃, 400 MHz): δ 8.12 (d, J = 1.5 Hz, 1H),7.34 (d, J = 1.5 Hz, 1H), 4.03 (s, 3H), 3.98-4.02 (m, 2H), 1.85- 1.94(m, 2H), 1.35 (s, 12H), 1.05 (t, J = 7.5 Hz, 3H). LCMS m/z = 294 [MH]⁺.125

Preparation 162 1H NMR (CDCl₃, 400 MHz): δ 7.57 (d, J = 8.4 Hz, 1H),7.07 (d, J = 8.4 Hz, 1H), 4.00-3.96 (m, 3H), 3.93-3.89 (m, 3H), 1.37 (s,12H). 126

Preparation 170a ¹H NMR (CDCl₃, 400 MHz): δ 7.35-7.44 (m, 1H), 6.69 (dd,J = 0.9, 8.4 Hz, 1H), 4.07-4.16 (m, 2H), 3.88 (s, 3H), 1.33-1.40 (m,15H). 127

Preparation 168 ¹H NMR (CDCl₃, 400 MHz): δ 7.15-7.18 (m, 1H), 7.11 (s,1H), 4.14 (q, J = 7.0 Hz, 2H), 3.96 (d, J = 1.3 Hz, 3H), 1.46 (t, J =7.0 Hz, 3H), 1.34 (s, 12H). ¹⁹F NMR (CDCl₃, 376 MHz): δ −114.25 (br s,1F). LCMS m/z = 296 [MH]⁺. 128

Preparation 170b LCMS m/z = 311 [MH]⁺. 129

Preparation 171 ¹H NMR (CDCl₃, 400 MHz): δ 7.54 (d, J = 8.1 Hz, 1H),7.05 (d, J = 8.3 Hz, 1H), 4.06-4.11 (m, 2H), 3.89 (s, 3H), 1.79-1.90 (m,2H), 1.35-1.38 (m, 12H), 1.03- 1.08 (m, 3H). LCMS m/z = 318 [MH]⁺. 130

Preparation 210 ¹H NMR (CDCl₃, 400 MHz): δ 7.42 (d, J = 8.5 Hz, 1H),6.69 (d, J = 8.3 Hz, 1H), 3.92-3.99 (m, 2H), 3.82- 3.87 (m, 6H),1.73-1.84 (m, 2H), 1.33-1.38 (m, 12H), 1.00-1.08 (m, 3H). LCMS m/z = 345[M + Na]⁺. 131

Preparation 207 ¹H NMR (CDCl₃, 400 MHz): δ 7.52 (d, J = 8.3 Hz, 1H),7.00-7.10 (m, 1H), 4.98- 5.11 (m, 1H), 3.88 (s, 3H), 1.91-2.01 (m, 4H),1.65- 1.76 (m, 2H), 1.53-1.64 (m, 2H), 1.37 (s, 12H). LCMS m/z = 344[MH]⁺. 132

Preparation 172 ¹H NMR (CDCl₃, 400 MHz): δ 7.17 (dd, J = 1.0, 10.5 Hz,1H), 7.11 (s, 1H), 4.14 (q, J = 7.0 Hz, 2H), 3.96 (d, J = 1.0 Hz, 3H),1.56 (s, 6H), 1.46 (t, J = 7.0 Hz, 3H), 1.34 (s, 12H). LCMS m/z = 297[MH]⁺. 133

Preparation 177 ¹H NMR (CDCl₃, 400 MHz): δ 7.44 (d, J = 1.0 Hz, 1H),7.22 (d, J = 1.0 Hz, 1H), 4.10-4.17 (m, 2H), 3.91 (s, 3H), 1.46 (t, J =7.0 Hz, 3H), 1.34 (s, 12H). LCMS m/z = 312 [MH]⁺. 134

Preparation 182 ¹H NMR (CDCl₃, 400 MHz): δ 7.14 (d, J = 5.5 Hz, 1H),6.59 (d, J = 10.0 Hz, 1H), 4.02-4.16 (m, 2H), 3.86 (s, 3H), 1.40-1.52(m, 3H), 1.34 (s, 12H). LCMS m/z = 297 [MH]⁺. 135

Preparation 183 ¹H NMR (CDCl₃, 400 MHz): δ 7.18 (s, 1H), 6.86 (s, 1H),4.12 (q, J = 7.0 Hz, 2H), 3.87 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H), 1.36(s, 12H). LCMS m/z = 312 [MH]⁺. 136

Preparation 187 ¹H NMR (CDCl₃, 400 MHz): δ 7.28 (s, 1H), 6.69 (s, 1H),4.13 (q, J = 6.9 Hz, 2H), 3.88 (s, 3H), 2.50 (s, 3H), 1.46 (t, J = 7.1Hz, 3H), 1.33 (s, 12H). LCMS m/z = 292 [MH]⁺. 137

Preparation 193 ¹H NMR (CDCl₃, 400 MHz): δ 6.34-6.48 (m, 1H), 4.04 (q, J= 7.0 Hz, 2H), 3.85 (s, 3H), 1.32-1.42 (m, 15H). LCMS m/z = 315 [MH]⁺.138

Preparation 188 ¹H NMR (CDCl₃, 400 MHz): δ 7.15 (d, J = 5.9 Hz, 1H),6.59 (d, J = 10.8 Hz, 1H), 3.98 (t, J = 6.8 Hz, 2H), 3.87 (s, 3H),1.81-1.90 (m, 2H), 1.25-1.30 (m, 12H), 1.05 (t, J = 7.6 Hz, 3H). 139

Preparation 198 ¹H NMR (CDCl₃, 400 MHz): δ 7.41 (dd, J = 1.2, 8.1 Hz,1H), 7.29 (d, J = 1.5 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 4.14 (q, J =7.0 Hz, 2H), 3.92 (s, 3H), 1.48 (t, J = 6.9 Hz, 3H), 1.34-1.36 (m, 12H).LCMS m/z = 279 [MH]⁺. 140

Preparation 199 ¹H NMR (CDCl₃, 400 MHz): δ 7.37 (dd, J = 6.4, 8.3 Hz,1H), 6.64-6.73 (m, 1H), 4.07-4.18 (m, 2H), 3.90 (d, J= 1.0 Hz, 3H), 1.46(t, J = 6.9 Hz, 3H), 1.35 (s, 12H). LCMS m/z = 297 [MH]⁺. 141

Preparation 197 ¹H NMR (400 MHz, CDCl₃) δ 7.39 (dd, J = 1.2, 8.1 Hz,1H), 7.30 (d, J = 1.0 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 4.08-4.17 (m,4H), 1.41-1.49 (m, 6H), 1.33 (s, 12H). LCMS m/z = 293 [MH]⁺. 142

Preparation 223 ¹H NMR (CDCl₃, 400 MHz): δ 7.40 (d, J = 1.2 Hz, 1H),7.38 (s, 1H), 7.15 (dd, J = 0.7, 7.6 Hz, 1H), 6.41-6.82 (m, 1H), 4.04(t, J = 6.5 Hz, 2H), 1.80-1.91 (m, 2H), 1.33-1.37 (m, 12H), 1.06 (t, J =7.3 Hz, 3H). 143

Preparation 203 ¹H NMR (CDCl₃, 400 MHz): δ 7.43 (dd, J = 1.1, 7.7 Hz,1H), 7.22 (s, 1H), 7.13 (d, J = 7.8 Hz, 1H), 3.95 (s, 3H), 2.45 (s, 3H),1.35 (s, 12H). LCMS m/z = 281 [MH]⁺. 144

Preparation 204 ¹H NMR (MeOD-d₃, 400 MHz): δ 7.34 (dd, J = 0.7, 7.6 Hz,1H), 7.19 (s, 1H), 7.12-7.16 (m, 1H), 4.10 (q, J = 7.1 Hz, 2H), 2.39 (d,J = 1.0 Hz, 3H), 1.39-1.44 (m, 3H), 1.34 (s, 12H). LCMS m/z = 295 [MH]⁺.145

Preparation 205 ¹H NMR (CDCl₃, 400 MHz): δ 7.39 (dd, J = 1.0, 7.8 Hz,1H), 7.22 (s, 1H), 7.06- 7.11 (m, 1H), 4.94-4.98 (m, 1H), 2.41 (s, 3H),1.82- 1.96 (m, 6H), 1.61-1.67 (m, 2H), 1.32-1.37 (m, 12H). LCMS m/z =335 [MH]⁺.

Preparation 146:tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane

Method A:

Five reactions were carried out in parallel. A mixture of((2-bromoallyl)oxy)(tert-butyl)dimethylsilane (Preparation 227, 300 g,1.19 mol), KOAc (234 g, 2.39 mol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (333 g, 1.31mol) and Pd(PPh₃)₂Cl₂ (16.7 g, 0.023 mol) in 1,4-dioxane (1.5 L) wasdegassed and stirred at about 80° C. for about 16 h. The solids wereremoved by filtration and the filtrate was concentrated. The residue waspurified by column chromatography (silica) and eluted with pet.ether/EtOAc (1:0) to affordtert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane(520 g, 30%). GC (Column: Agilent J&W HP-5MS 30M×0.25 mm ID×0.25 um filmthickness; injector temp. 250° C.; split ratio 100:1; ion source temp230° C.; interface temp. 250° C.; Column temp. 50° C. 1 min to 100° C. @30° C./min to 250° C. @ 10° C./min.; run time 17.67 min.; Flow rate 1.5mL/min; RT=11.67 min. ¹H NMR (CDCl₃, 400 MHz): δ 5.97 (d, J=1.3 Hz, 1H),5.88 (td, J=1.8, 3.9 Hz, 1H), 4.29 (t, J=2.0 Hz, 2H), 1.21-1.30 (m,12H), 0.93 (s, 9H), 0.07 (s, 6H).

Method B:

To a mixture of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (250 mg,1.47 mmol), sodium t-butoxide (21.2 mg, 0.220 mmol), copper (I) chloride(14.5 mg, 0.10 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (410 mg,1.61 mmol) under N₂ was added dropwise a solution of tBu₃P (1.0Msolution in toluene, 0.176 mL, 0.12 mmol) in anhydrous toluene (2.5 mL).MeOH (94 mg, 2.94 mmol) was added to the mixture dropwise and themixture was stirred at about 20° C. overnight. The reaction was quenchedwith MeOH (20 mL) and concentrated. The residue was purified by columnchromatography (silica) and eluted with pet. ether/EtOAc (100:0 to80:20) to affordtert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane(2.2 g, 50%). ¹H NMR (CDCl₃, 400 MHz): δ 5.97 (br s, 1H), 5.88 (d, J=1.6Hz, 1H), 4.29 (s, 2H), 1.25-1.33 (m, 12H), 0.93 (s, 9H), 0.08 (s, 6H).

Preparation 147:tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-yl)oxy)silane

To a mixture of (but-3-yn-2-yloxy)(tert-butyl)dimethylsilane (CAS193812-02-1, 10 g, 54.24 mmol), sodium t-butoxide (782 mg, 8.41 mmol),copper (I) chloride (537 mg, 5.42 mmol) and Pin₂B₂ (15.2 g, 59.7 mmol)in toluene (120 mL) under N₂ was added a solution of tBu₃P (13.2 g, 6.51mmol) in anhydrous toluene (10 mL) drop-wise. MeOH (3.48 g, 108 mmol)was added dropwise and the mixture was stirred at about 20° C. for about16 h. The reaction was quenched with MeOH (10 mL) and concentrated. Theresidue was purified by column chromatography (silica) and eluted withpet. ether/EtOAc (100:0 to 97:3) to affordtert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-yl)oxy)silane(8.2 g, 48.4%). ¹H NMR (CDCl₃, 400 MHz): δ 5.88-6.02 (m, 1H), 5.79 (dd,J=1.5, 3.5 Hz, 1H), 4.40-4.56 (m, 1H), 1.27 (d, J=3.5 Hz, 12H), 1.24 (d,J=6.5 Hz, 3H), 0.91 (s, 9H), 0.05 (d, J=5.5 Hz, 6H).

Preparation 148:tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane

A mixture of ((3-bromobut-3-en-1-yl)oxy)(tert-butyl)dimethylsilane(Preparation 229, 2.0 g, 7.54 mmol), Pin₂B₂ (2.87 g, 11.3 mmol) and KOAc(0.74 g, 7.54 mmol) was suspended in anhydrous 1,4-dioxane (10 mL). Themixture was degassed for about 10 min at about 18° C. under N₂.Pd(PPh)₂Cl₂ (106 mg, 0.15 mmol) was added and the mixture was heated toabout 90° C. for 16 h. The reaction was cooled to about 20° C. andfiltered. The filter cake was washed with 1,4-dioxane and the combinedfiltrates were concentrated. The residue was purified by columnchromatography (silica) and eluted with heptane/EtOAc (100:0 to 80:20)to affordtert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane(1.15 g, 49%). LCMS m/z=313 [MH]⁺.

Preparation 149:2,2′-(ethane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)

A mixture of 1,1-dibromoethane (14.9 g, 58.6 mmol), lithium methoxide(3.03 g, 79.8 mmol) and copper (I) iodide (5.07 g, 26.6 mmol) wassuspended in DMF (150 mL) under N₂. Additional lithium methoxide (5.0 g,2.43 mL) in DMF (10 mL) was added to the mixture. The reaction mixturewas warmed to about 40° C. and stirred for about 48 h under N₂. Thesolution was cooled to to about 20° C. and extracted with heptane (3×300mL). The heptane extracts were washed with water (100 mL), brine (100mL) and passed through a pad of MgSO₄ and silica gel. The pad was washedwith DCM (100 mL). The combined filtrates were concentrated. The residuewas purified by column chromatography (silica) and eluted with DCM toafford 2,2′-(ethane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane(3.6 g, 48%). ¹H NMR (CDCl₃, 400 MHz): δ 1.23 (d, J=3.1 Hz, 24H), 1.05(d, J=7.4 Hz, 3H), 0.72 (q, J=7.0 Hz, 1H).

Preparation 150: 4-bromo-2-ethoxy-1-methoxybenzene

A mixture of 5-bromo-2-methoxyphenol (40.0 g, 197.0 mmol), iodoethane(23.6 mL, 295.5 mmol) and Cs₂CO₃ (96.3 g, 295.5 mmol) in DMF (350 mL)was stirred at about 25° C. for about 16 h. The mixture was filtered andwater (500 mL) was added to the filtrate. The mixture was extracted withEtOAc (2×400 mL). The combined EtOAc extracts were washed with brine(100 mL), dried over Na₂SO₄ and concentrated. The residue was purifiedby column chromatography (silica) and eluted with pet. ether/EtOAc(10:1) to afford 4-bromo-2-ethoxy-1-methoxybenzene (48.0 g), which wasused directly in the next step. ¹H NMR (CDCl₃, 400 MHz): δ 7.02 (dd,J=2.4, 8.4 Hz, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.76-6.73 (m, 1H), 4.08 (q,J=7.2 Hz, 2H), 3.88 (s, 3H), 1.47 (t, J=7.2 Hz, 3H).

Preparation 151: 4-bromo-1-methoxy-2-propoxybenzene

To a solution of 5-bromo-2-methoxyphenol (40.0 g, 197.0 mmol) and K₂CO₃(54.5 g, 394 mmol) in DMF (200 mL) was added 1-iodopropane (28.9 mL, 295mmol) in portions at about 20° C. The mixture was stirred at about 20°C. for about 1 h. The mixture was poured into ice water (500 mL) andextracted with EtOAc (3×300 mL). The combined EtOAc extracts were washedwith brine (200 mL), dried over Na₂SO₄ and concentrated. The residue waspurified by column chromatography (silica) and eluted with pet.ether/EtOAc (40:1) to afford 4-bromo-1-methoxy-2-propoxybenzene (43.0 g,crude). ¹H NMR (CDCl₃, 400 MHz): δ 7.27 (s, 1H), 6.99-7.03 (m, 1H), 6.74(d, J=8.4 Hz, 1H), 3.96 (t, J=6.8 Hz, 2H), 3.85 (s, 3H), 1.83-1.92 (m,2H), 1.05 (t, J=7.6 Hz, 3H).

Preparation 152: 4-bromo-2-isopropoxy-1-methoxybenzene

4-bromo-2-isopropoxy-1-methoxybenzene (16 g, 95%) was prepared in ananalogous manner to Preparation 150 using 2-bromopropane (12.7 g, 103.4mmol). ¹H NMR (CDCl₃, 400 MHz): δ 7.00-7.05 (m, 2H), 6.75 (d, J=8.3 Hz,1H), 4.50-4.54 (m, 1H), 3.83 (s, 3H), 1.35-1.40 (m, 6H). LCMS m/z=245[MH]⁺.

Preparation 153: 4-bromo-2-isobutoxy-1-methoxybenzene

To a solution of 5-bromo-2-methoxyphenol (25 g, 120 mmol),2-methylpropan-1-ol (11.0 g, 148 mmol), PPh₃ (48.4 g, 185 mmol) inanhydrous DCM (400 mL) at about 0° C. was added DIAD (37.3 g, 185 mmol)dropwise under N₂. The mixture was stirred at about 0° C. for about 2 h.Additional DIAD (2.53 g, 12.5 mmol) and 2-methylpropan-1-ol (1.03 g,13.9 mmol) were added and the mixture was stirred at about 10° C. forabout 5 days then filtered. The filtrate was concentrated under reducedpressure. MTBE (500 mL) was added and the mixture was stirred at about10° C. for about 20 min. A white precipitate was filtered. The filtratewas concentrated. The residue was dissolved in water (200 mL) andextracted with MTBE (2×300 mL). The combined MTBE extracts wereconcentrated and the residue was purified by column chromatography(silica) and eluted with pet. ether/EtOAc (100:1 to 90:10) to afford4-bromo-2-isobutoxy-1-methoxybenzene (22 g, 69%). ¹H NMR (CDCl₃, 400MHz): δ 6.99-7.03 (m, 1H), 6.96-6.99 (m, 1H), 6.74 (d, J=8.5 Hz, 1H),3.84 (s, 3H), 3.75 (d, J=7.0 Hz, 2H), 2.11-2.22 (m, 1H), 1.04 (d, J=6.5Hz, 6H).

Preparation 154: 4-bromo-2-cyclopropoxy-1-methoxybenzene

4-bromo-2-cyclopropoxy-1-methoxybenzene (6.15 g, 64%) was prepared in ananalogous manner to Preparation 150 using bromocyclopropane (8.0 g, 39mmol). ¹H NMR (CDCl₃, 400 MHz): δ 7.36 (d, J=2.5 Hz, 1H), 7.05 (dd,J=2.5, 8.5 Hz, 1H), 6.74 (d, J=8.5 Hz, 1H), 3.84 (s, 3H), 3.70-3.77 (m,1H), 0.80-0.90 (m, 4H).

Preparation 155: 3-(5-bromo-2-methoxyphenoxy)tetrahydrothiophene

To a solution of 5-bromo-2-methoxyphenol (1.6 g, 7.88 mmol),tetrahydrothiophen-3-ol (0.903 g, 8.67 mmol), PPh₃ (3.10 g, 11.8 mmol)in anhydrous DCM (20 mL) at about 0° C. was added DIAD (2.39 g, 11.8mmol) dropwise under N₂. The mixture was stirred at about 0° C. forabout 2 h. The mixture was stirred for about 3 days. The mixture wasfiltered and the filtrate was concentrated. To the residue was addedMTBE (50 mL) and stirred at about 10° C. for about 20 min. A whiteprecipitate was filtered. The filtrate was concentrated again. Theresidue was dissolved in water (20 mL) and extracted with MTBE (2×30mL). The combined MTBE extracts were concentrated and the residue waspurified by column chromatography (silica) and eluted with pet.ether/EtOAc (100:1 to 90:10) to afford3-(5-bromo-2-methoxyphenoxy)tetrahydrothiophene (2.0 g, 88%). ¹H NMR(CDCl₃, 400 MHz): δ 7.05-7.11 (m, 2H), 6.74-6.79 (m, 1H), 5.06-5.09 (m,1H), 3.82 (s, 3H), 3.04-3.15 (m, 3H), 2.93 (ddd, J=3.7, 7.3, 10.5 Hz,1H), 2.38-2.47 (m, 1H), 2.03-2.05 (m, 1H).

Preparation 156: 4-(5-bromo-2-methoxyphenoxy) tetrahydro-2H-thiopyran

4-(5-bromo-2-methoxyphenoxy) tetrahydro-2H-thiopyran (5.1 g, 68%) wasprepared in an analogous manner to Preparation 155 usingtetrahydro-2H-thiopyran-4-ol (3.2 g, 27.1 mmol). ¹H NMR (CDCl₃, 400MHz): δ 7.03-7.08 (m, 1H), 7.01 (d, J=2.5 Hz, 1H), 6.73-6.77 (m, 1H),4.21-4.29 (m, 1H), 3.81-3.84 (m, 3H), 2.87-2.96 (m, 2H), 2.52-2.62 (m,2H), 2.15-2.25 (m, 2H), 1.98-2.08 (m, 2H).

Preparation 157:(2-(5-bromo-2-methoxyphenoxy)ethoxy)(tert-butyl)dimethylsilane

(2-(5-bromo-2-methoxyphenoxy)ethoxy)(tert-butyl)dimethylsilane (60 g,86%) was prepared in an analogous manner to Preparation 155 using2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (34 g, 190 mmol). ¹H NMR(CDCl₃, 400 MHz): δ 7.07 (d, J=2.2 Hz, 1H), 7.00-7.05 (m, 1H), 6.71-6.76(m, 1H), 4.06-4.11 (m, 2H), 3.96-4.02 (m, 2H), 3.81-3.85 (m, 3H),0.88-0.93 (m, 9H), 0.08-0.12 (m, 6H).

Preparation 158:(3-(5-bromo-2-methoxyphenoxy)propoxy)(tert-butyl)dimethylsilane

(3-(5-bromo-2-methoxyphenoxy)propoxy)(tert-butyl)dimethylsilane (19.8 g,86%) was prepared in an analogous manner to Preparation 155 using3-((tert-butyldimethylsilyl)oxy)propan-1-ol (Preparation 236, 12.5 g,61.6 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 6.99-7.03 (m, 2H), 6.71-6.75 (m,1H), 4.08-4.13 (m, 2H), 3.83 (s, 3H), 3.81 (t, J=5.9 Hz, 2H), 2.00-2.07(m, 2H), 0.88-0.91 (m, 9H), 0.04-0.07 (m, 6H).

Preparation 159: 4-bromo-2-(2-fluoroethoxy)-1-methoxybenzene

4-bromo-2-(2-fluoroethoxy)-1-methoxybenzene (12 g, 98%) was prepared inan analogous manner to Preparation 155 using 2-fluoroethan-1-ol (3.79 g,59 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 7.08 (dd, J=2.5, 8.8 Hz, 1H), 7.03(d, J=2.5 Hz, 1H), 6.75-6.79 (m, 1H), 4.82-4.87 (m, 1H), 4.71-4.74 (m,1H), 4.27-4.31 (m, 1H), 4.20-4.24 (m, 1H), 3.86 (s, 3H).

Preparation 160: 4-bromo-2-(3-fluoropropoxy)-1-methoxybenzene

4-bromo-2-(3-fluoropropoxy)-1-methoxybenzene (10 g, 100%) was preparedin an analogous manner to Preparation 155 using 3-fluoropropan-1-ol(3.69 g, 47.3 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 7.03-7.07 (m, 1H),7.01-7.03 (m, 1H), 6.75 (d, J=8.3 Hz, 1H), 4.72 (t, J=5.6 Hz, 1H), 4.61(t, J=5.6 Hz, 1H), 4.13 (t, J=6.1 Hz, 2H), 3.84 (s, 3H), 2.26-2.28 (m,1H), 2.19-2.22 (m, 1H).

Preparation 161: 1-bromo-2-fluoro-3,4-dimethoxybenzene

A mixture of 1-fluoro-2,3-dimethoxybenzene (35.0 g, 224.1 mmol) and NBS(43.9 g, 246.6 mmol) in DCM (300 mL) was degassed and stirred at about15° C. for about 12 h under N₂. The reaction mixture was quenched withwater (300 mL) and extracted with DCM (2×300 mL). The combined DCMextracts were washed with brine (2×100 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by column chromatography(silica) and eluted with pet. ether/EtOAc (10:1) to afford1-bromo-2-fluoro-3,4-dimethoxybenzene (35.0 g, 66%). ¹H NMR (CDCl₃, 400MHz): δ 7.17-7.21 (m, 1H), 6.60-6.63 (m, 1H), 3.93 (s, 3H), 3.87 (s,3H).

Preparation 162: 6-bromo-2,3-dimethoxybenzonitrile

To a solution of 6-bromo-2,3-dimethoxybenzaldehyde oxime (Preparation163, 30.0 g, 115 mmol) in DCM (500 mL) was added TFAA (24.0 mL, 173mmol) and Et₃N (48.0 mL, 346.0 mmol). The mixture was stirred at about20° C. for about 2 h. The mixture was quenched with water (200 mL) atabout 0° C. and extracted with DCM (300 mL). The combined DCM extractswere washed with brine, dried over Na₂SO₄, filtered and concentrated.The residue was purified by column chromatography (silica) and elutedwith pet. ether/EtOAc (10:1 to 3:1) to afford6-bromo-2,3-dimethoxybenzonitrile (25.0 g, 90%). ¹H NMR (CDCl₃, 400MHz): δ 7.34-7.29 (m, 1H), 6.99 (d, J=8.8 Hz, 1H), 4.04-4.01 (m, 3H),3.90-3.88 (m, 3H).

Preparation 163: 6-bromo-2,3-dimethoxybenzaldehyde oxime

To a solution of 6-bromo-2,3-dimethoxybenzaldehyde (Preparation 164,15.0 g, 61.2 mmol) in EtOH (150 mL) was added NaHCO₃ (7.7 g, 91.8 mmol)and NH₂OH.HCl (6.4 g, 91.8 mmol). The mixture was stirred at about 20°C. for about 2 h. The mixture was quenched by the addition of water (300mL) at about 0° C. and extracted with EtOAc (200 mL). The EtOAc layerwas washed with brine, dried over Na₂SO₄, filtered and concentrated toafford 6-bromo-2,3-dimethoxybenzaldehyde oxime (15.0 g), which was usedin Preparation 162. ¹H NMR (CDCl₃, 400 MHz): δ 7.27-7.34 (m, 1H), 6.99(d, J=9.2 Hz, 1H), 4.00-4.03 (m, 3H), 3.87-3.90 (m, 3H).

Preparation 164: 6-bromo-2,3-dimethoxybenzaldehyde

6-bromo-2,3-dimethoxybenzaldehyde (35.0 g, 82.5%) was prepared in ananalogous manner to Preparation 172 using6-bromo-2-hydroxy-3-methoxybenzaldehyde (Preparation 165, 40 g, 173.1mmol) and iodomethane (36.8 g, 259.7 mmol). ¹H NMR (CDCl₃, 400 MHz): δ10.35 (s, 1H), 7.33-7.37 (m, 1H), 6.97 (d, J=8.8 Hz, 1H), 3.94 (s, 3H),3.90 (s, 3H).

Preparation 165: 6-bromo-2-hydroxy-3-methoxybenzaldehyde

To a solution of 3-bromo-2-formyl-6-methoxyphenyl acetate (Preparation166, 40.0 g, 146.5 mmol) in MeOH (400 mL) and water (50 mL) was addedNaHCO₃ (13.5 g, 161.1 mmol) and LiOH (12.3 g, 293.0 mmol). The mixturewas stirred at about 20° C. for about 12 h. The reaction was adjusted topH 5-6 and extracted with DCM. The DCM layer was concentrated to afford6-bromo-2-hydroxy-3-methoxybenzaldehyde (40.0 g), which was used inPreparation 164. ¹H NMR (CDCl₃, 400 MHz): δ 12.21 (s, 1H), 10.22 (s,1H), 7.03 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 3.81-3.85 (m, 3H).

Preparation 166: 3-bromo-2-formyl-6-methoxyphenyl acetate

To a solution of 2-formyl-6-methoxyphenyl acetate (Preparation 167, 50.0g, 257.5 mmol) in water (500 mL) was added Br₂ (53.5 g, 334.7 mmol) andKBr (46.0 g, 386.2 mmol). The mixture was stirred at about 20° C. forabout 10 h. The precipitate was filtered, rinsed with ethyl acetate andrecrystallized from EtOAc/pet. ether to afford3-bromo-2-formyl-6-methoxyphenyl acetate (40.0 g, 57%). ¹H NMR (CDCl₃,400 MHz): δ 10.28 (s, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.07 (d, J=8.8 Hz,1H), 3.87 (s, 3H), 2.40 (s, 3H).

Preparation 167: 2-formyl-6-methoxyphenyl acetate

To a solution of 2-hydroxy-3-methoxybenzaldehyde (50.0 g, 328.6 mmol) inDCM (200 mL) was added Ac₂O (33.5 g, 329 mmol), DMAP (4.0 g, 32.8 mmol)and Et₃N (33.2 g, 329 mmol). The mixture was stirred at about 20° C. forabout 2 h. The reaction mixture was quenched with saturated aqueousNH₄Cl (100 mL) and extracted with DCM (2×100 mL). The combined DCMextracts were washed with HCl (100 mL, 1 M), brine (300 mL), dried overNa₂SO₄, filtered and concentrated to afford 2-formyl-6-methoxyphenylacetate (60.0 g, 94%). ¹H NMR (CDCl₃, 400 MHz): δ 10.12-10.17 (m, 1H),7.46 (dd, J=1.6, 7.8 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), 7.22 (dd, J=1.6,8.2 Hz, 1H), 3.88 (s, 3H), 2.41 (s, 3H).

Preparation 168: 1-bromo-2-(difluoromethyl)-3-ethoxy-4-methoxybenzene

To a mixture of DAST (CAS 38078-09-0, 17.8 mL, 143.0 mmol) in DCM (100mL) was added a solution of 6-bromo-2-ethoxy-3-methoxybenzaldehyde(Preparation 169, 4.64 g, 17.9 mmol) in DCM (20 mL) at about −20° C. Thereaction mixture was warmed to about 25° C. over 0.5 h and then at about25° C. for about 15 h. The reaction was quenched with saturated aqueousNaHCO₃ (200 mL) at about 0° C. and the mixture was extracted with DCM(2×100 mL). The combined DCM extracts were concentrated and the residuewas purified by column chromatography (silica) and eluted with pet.ether/EtOAc (100:0 to 97:3) to afford1-bromo-2-(difluoromethyl)-3-ethoxy-4-methoxybenzene (4.77 g, 95%). ¹HNMR (CDCl₃, 400 MHz): δ 7.31 (d, J=8.8 Hz, 1H), 7.10 (t, J=54.0 Hz, 1H),6.87 (d, J=8.8 Hz, 1H), 4.11 (q, J=7.0 Hz, 2H), 3.87 (s, 3H), 1.40 (t,J=7.0 Hz, 3H).

Preparation 169: 6-bromo-2-ethoxy-3-methoxybenzaldehyde

To a mixture of 6-bromo-2-hydroxy-3-methoxybenzaldehyde (Preparation165, 5 g, 21.64 mmol) and K₂CO₃ (5.98 g, 43.3 mmol) in MeCN (100 mL) wasadded iodoethane (16.9 g, 108 mmol). The mixture was warmed to 60° C.and stirred for 4 h, followed by heating to 100° C. for 19 h. Themixture was cooled to r.t and condensed under reduced pressure. Theresidue was purified by column chromatography (silica) and eluted withpet. ether:EtOAc (100:0 to 90:10) to afford6-bromo-2-ethoxy-3-methoxybenzaldehyde (5.1 g, 92%) as a light yellowoil. ¹H NMR (CDCl₃, 400 MHz): δ 10.37 (s, 1H), 7.34 (d, J=8.8 Hz, 1H),6.96 (d, J=8.8 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.88 (s, 3H), 1.40 (t,J=7.0 Hz, 3H).

Preparation 170a: 1-bromo-3-ethoxy-2-fluoro-4-methoxybenzene

1-bromo-3-ethoxy-2-fluoro-4-methoxybenzene (25 g, 58%) was prepared inan analogous manner to Preparation 155 using3-bromo-2-fluoro-6-methoxyphenol (38 g, 170 mmol) and iodoethane (40.2g, 258 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 7.14-7.20 (m, 1H), 6.58-6.63(m, 1H), 4.02 (t, J=6.7 Hz, 2H), 3.86 (s, 3H), 1.75-1.80 (m, 2H), 1.03(t, J=7.5 Hz, 3H).

Preparation 170b: 1-bromo-2-fluoro-4-methoxy-3-propoxybenzene

1-bromo-2-fluoro-4-methoxy-3-propoxybenzene (10.2 g 57%) was prepared inan analogous manner to Preparation 155 using3-bromo-2-fluoro-6-methoxyphenol (15 g, 68.2 mmol) and 1-bromopropane(10.8 g, 88.6 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 7.14-7.20 (m, 1H),6.58-6.63 (m, 1H), 4.02 (t, J=6.7 Hz, 2H), 3.86 (s, 3H), 1.75-1.80 (m,2H), 1.03 (t, J=7.5 Hz, 3H).

Preparation 171: 6-bromo-3-methoxy-2-propoxybenzonitrile

6-bromo-3-methoxy-2-propoxybenzonitrile (10.9 g 92%) was prepared in ananalogous manner to Preparation 155 using6-bromo-2-hydroxy-3-methoxybenzonitrile (10 g, 44 mmol) and1-bromopropane (7 g, 57 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 7.27-7.30 (m,1H), 6.96 (d, J=8.8 Hz, 1H), 4.15 (t, J=6.6 Hz, 2H), 3.86 (s, 3H),1.78-1.87 (m, 2H), 1.06 (t, J=7.5 Hz, 3H). LCMS m/z=270 [MH]⁺.

Preparation 172: 5-bromo-1-ethoxy-3-fluoro-2-methoxybenzene

To a mixture of 5-bromo-3-fluoro-2-methoxyphenol (Preparation 173, 2.21g, 10.0 mmol) and iodoethane (3.12 g, 20.0 mmol) dissolved in MeCN (30mL) was added K₂CO₃ (2.07 g, 15 mmol). The mixture was warmed to about50° C. and stirred for about 5 h. The mixture was cooled to about 20° C.and was filtered. The filtrate was concentrated and the residue wastriturated with MTBE (20 mL) for about 20 min. The mixture was filteredand the filtrate was concentrated to afford5-bromo-1-ethoxy-3-fluoro-2-methoxybenzene (1.85 g, 74%). ¹H NMR (CDCl₃,400 MHz): δ 6.88-6.91 (m, 1H), 6.82-6.83 (m, 1H), 4.07 (q, J=7.0 Hz,2H), 3.90 (d, J=0.7 Hz, 3H), 1.46 (t, J=7.0 Hz, 3H).

Preparation 173: 5-bromo-3-fluoro-2-methoxyphenol

To a mixture 5-bromo-3-fluoro-2-methoxyphenyl formate (Preparation 174,4.98 g, 20.0 mmol) in MeOH (30 mL) and water (30 mL) was added LiOH(1.68 g, 40.0 mmol) in portions. The mixture was stirred at about 25° C.for about 16 h. The mixture was concentrated. The resulting aqueousphase was diluted with water and NaHCO₃ was added until pH 8. Theaqueous phase was washed with MTBE (2×30 mL) and the combine MTBEextracts were concentrated. The residue was purified by columnchromatography (silica) and eluted with pet. ether/EtOAc (100:0 to85:15) to afford 5-bromo-3-fluoro-2-methoxyphenol (2.4 g, 54% over 2steps). ¹H NMR (CDCl₃, 400 MHz): δ 6.91-6.92 (m, 1H), 6.81-6.84 (m, 1H),5.82 (s, 1H), 4.00 (d, J=1.8 Hz, 3H).

Preparation 174: 5-bromo-3-fluoro-2-methoxyphenyl formate

To a mixture of 5-bromo-3-fluoro-2-methoxybenzaldehyde (Preparation 175,3.50 g, 15.0 mmol) in DCM (50 mL) was added m-CPBA (4.85 g, 22.5 mmol).The resulting mixture was stirred at about 25° C. for about 16 h. Thereaction was concentrated to afford2-(5-bromo-3-fluoro-2-methoxyphenyl)acetaldehyde (3.74 g), which wasused in Preparation 173.

Preparation 175: 5-bromo-3-fluoro-2-methoxybenzaldehyde

To a mixture of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (Preparation 176,18.6 g, 85.0 mmol) in MeCN (150 mL) was added K₂CO₃ (17.6 g, 128.0 mmol)and iodomethane (24.1 g, 170.0 mmol). The mixture was warmed to about50° C. for about 16 h. The reaction was filtered and the filtrate wasconcentrated. The residue was triturated in MTBE (50 mL) and theresulting solid was filtered to afford5-bromo-3-fluoro-2-methoxybenzaldehyde (4.9 g, 25%). ¹H NMR (CDCl₃, 400MHz): δ 10.33 (s, 1H), 7.73-7.74 (m, 1H), 7.47-7.51 (m, 1H), 4.10 (d,J=3.0 Hz, 3H).

Preparation 176: 5-bromo-3-fluoro-2-hydroxybenzaldehyde

To a mixture of 4-bromo-2-fluorophenol (20.0 g, 104.7 mmol) dissolved inTFA (100 mL) was added HMTA (CAS 100-97-0, 29.4 g, 209.0 mmol) inportions. The mixture was heated at about 90° C. for about 16 h. Themixture was poured into water (800 mL) and a solid formed which wasfiltered. The cake was washed with water (2×150 mL) and dried to afford5-bromo-3-fluoro-2-hydroxybenzaldehyde (18.9 g, 82%). ¹H NMR (CDCl₃, 400MHz): δ 10.90 (s, 1H), 9.88 (d, J=2.0 Hz, 1H), 7.49-7.53 (m, 2H).

Preparation 177: 5-bromo-1-chloro-3-ethoxy-2-methoxybenzene

5-bromo-1-chloro-3-ethoxy-2-methoxybenzene (1.25 g, 86%) was prepared inan analogous manner to Preparation 172 using5-bromo-3-chloro-2-methoxyphenol (Preparation 178, 1.3 g, 5.47 mmol). ¹HNMR (CDCl₃, 400 MHz): δ 7.12 (d, J=2.3 Hz, 1H), 6.93 (d, J=2.3 Hz, 1H),4.06 (q, J=7.0 Hz, 2H), 3.86 (s, 3H), 1.46 (t, J=7.0 Hz, 3H).

Preparation 178: 5-bromo-3-chloro-2-methoxyphenol

To a mixture of 5-bromo-3-chloro-2-methoxyphenyl formate (Preparation179, 15.6 g, 58.76 mmol) in MeOH (100 mL) and water (100 mL) was addedLiOH (4.93 g, 118.0 mmol) in portions. The mixture was stirred at about25° C. for about 16 h. The mixture was concentrated and the resultingaqueous phase was diluted with aqueous NaHCO₃ (50 mL). The solution wasextracted with MTBE (2×30 mL) and the combined MTBE extracts were driedand concentrated. The residue was purified by column chromatography(silica) and eluted with pet. ether:EtOAc (100:0 to 90:10) to afford5-bromo-3-chloro-2-methoxyphenol (1.3 g, 7% over 2 steps). ¹H NMR(CDCl₃, 400 MHz): δ 7.07 (d, J=2.3 Hz, 1H), 7.05 (d, J=2.3 Hz, 1H), 5.79(s, 1H), 3.92 (s, 3H).

Preparation 179: 5-bromo-3-chloro-2-methoxyphenyl formate

To a mixture of 5-bromo-3-chloro-2-methoxybenzaldehyde (Preparation 180,20.0 g, 80.16 mmol) in DCM (200 mL) was added m-CPBA (25.9 g, 120 mmol).The mixture was stirred at about 25° C. for about 16 h. The white solidwas filtered and the filtrate was concentrated to afford5-bromo-3-chloro-2-methoxyphenyl formate (15.0 g, 70%), which was usedin Preparation 178. LCMS m/z=266 [MH]⁺.

Preparation 180: 5-bromo-3-chloro-2-methoxybenzaldehyde

To a mixture of 5-bromo-3-chloro-2-hydroxybenzaldehyde (Preparation 181,10 g, 42.5 mmol) dissolved in MeCN (150 mL) was added iodomethane (24.1g, 170 mmol) and K₂CO₃ (11.7 g, 84.9 mmol). The mixture was warmed toabout 50° C. and stirred for about 24 h. The mixture was cooled to about20° C., filtered. The filtrate was concentrated and the residue wastriturated with MTBE (30 mL) for about 20 min. before filtering. Thefiltrate was concentrated and the residue was diluted with water (20 mL)and extracted with EtOAc (2×100 mL). The combined EtOAc extracts wereconcentrated to afford 5-bromo-3-chloro-2-methoxybenzaldehyde (8.9 g,84%), which was used in Preparation 179. ¹H NMR (CDCl₃, 400 MHz): δ10.30 (s, 1H), 7.87 (d, J=2.5 Hz, 1H), 7.77 (d, J=2.5 Hz, 1H), 4.01 (s,3H).

Preparation 181: 5-bromo-3-chloro-2-hydroxybenzaldehyde

To a mixture of 4-bromo-2-chlorophenol (20.0 g, 94.41 mmol) in TFA (150mL) was added HMTA (CAS 100-97-0, 27.0 g, 193 mmol) in portions. Themixture was stirred at about 90° C. for about 16 h. The mixture waspoured into water (800 mL) forming a precipitate. The precipitate wasfiltered, washed with water (2×150 mL) and dried to afford5-bromo-3-chloro-2-hydroxybenzaldehyde (22.7 g), which was used inPreparation 180. ¹H NMR (CDCl₃, 400 MHz): δ 11.40 (br s, 1H), 9.86 (s,1H), 7.75 (d, J=2.3 Hz, 1H), 7.63 (d, J=2.3 Hz, 1H).

Preparation 182: 1-bromo-5-ethoxy-2-fluoro-4-methoxybenzene

1-bromo-5-ethoxy-2-fluoro-4-methoxybenzene (7.1 g, 90%) was prepared inan analogous manner to Preparation 172 using5-bromo-4-fluoro-2-methoxyphenol (Preparation 192, 7.0 g, 32.0 mmol). ¹HNMR (CDCl₃, 400 MHz): δ 6.96-6.98 (m, 1H), 6.69-6.71 (m, 1H), 4.02-4.07(m, 2H), 3.84 (s, 3H), 1.41-1.52 (m, 3H).

Preparation 183: 1-bromo-2-chloro-5-ethoxy-4-methoxybenzene

1-bromo-2-chloro-5-ethoxy-4-methoxybenzene (5.7 g, 98%) was prepared inan analogous manner to Preparation 172 using5-bromo-4-chloro-2-methoxyphenol (Preparation 184, 5.2 g, 21.9 mmol). ¹HNMR (CDCl₃, 400 MHz): δ 7.05 (s, 1H), 6.94 (s, 1H), 4.06 (q, J=7.0 Hz,2H), 3.86 (s, 3H), 1.47 (t, J=7.0 Hz, 3H).

Preparation 184: 5-bromo-4-chloro-2-methoxyphenol

To a mixture of 5-bromo-4-chloro-2-methoxyphenyl formate (Preparation185, 3.2 g, 12.05 mmol) in MeOH (50 mL) and water (50 mL) was added NaOH(0.72 g, 18.1 mmol). The mixture was stirred at about 20° C. for about 1h. The mixture was acidified using 1N HCl to pH 3. The mixture wasconcentrated and the remaining aqueous phase was extracted with EtOAc(3×100 mL). The combined EtOAc extracts were washed with brine (200 mL),dried with anhydrous Na₂SO₄, filtered and concentrated to afford5-bromo-4-chloro-2-methoxyphenol (2.8 g, 98%). ¹H NMR (CDCl₃, 400 MHz):δ 7.16 (s, 1H), 6.93 (s, 1H), 5.58 (s, 1H), 3.28 (s, 3H).

Preparation 185: 5-bromo-4-chloro-2-methoxyphenyl formate

To a mixture of 5-bromo-4-chloro-2-methoxybenzaldehyde (Preparation 186,12.2 g, 48.9 mmol) in DCM (300 mL) was added m-CPBA (21.1 g, 97.8 mmol).The mixture was stirred at about 18° C. for about 16 h. The mixture waspartitioned between DCM (400 mL) and saturated sodium metabisulfitesolution (200 mL). The separated DCM layer was washed with water (400mL), brine (400 mL), dried over MgSO₄ and concentrated. The residue waspurified by column chromatography (silica) and eluted with pet.ether/EtOAc (100:0 to 90:10) to afford 5-bromo-4-chloro-2-methoxyphenylformate (3.2 g, 25%). ¹H NMR (CDCl₃, 400 MHz): δ 8.22 (s, 1H), 7.36 (s,1H), 7.09 (s, 1H), 3.85 (s, 3H).

Preparation 186: 5-bromo-4-chloro-2-methoxybenzaldehyde

To a mixture of 1-bromo-2-chloro-4-methoxybenzene (15.0 g, 67.73 mmol)in TFA (100 mL) was added HMTA (CAS 100-97-0, 14.2 g, 102 mmol) inportions. The mixture was stirred at about 80° C. for about 12 h. Themixture was poured into water (1000 mL) and stirred at about 20° C. forabout 1 h, forming a precipitate. The precipitate was filtered,dissolved in EtOAc (200 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (silica)and eluted with pet. ether/EtOAc (100:0 to 90:10) to afford5-bromo-4-chloro-2-methoxybenzaldehyde (6.7 g, 40%). ¹H NMR (CDCl₃, 400MHz): δ 10.33 (s, 1H), 8.03 (s, 1H), 7.12 (s, 1H), 3.94 (s, 3H).

Preparation 187: 1-bromo-5-ethoxy-4-methoxy-2-methylbenzene

1-bromo-5-ethoxy-4-methoxy-2-methylbenzene (8.0 g, 99%) was prepared inan analogous manner to Preparation 172 using5-bromo-2-methoxy-4-methylphenol (Preparation 189, 7.16 g, 33.0 mmol).¹H NMR (CDCl₃, 400 MHz): δ 7.01 (s, 1H), 6.74 (s, 1H), 4.05 (q, J=7.0Hz, 2H), 3.85 (s, 3H), 2.33 (s, 3H) 1.46 (t, J=7.0 Hz, 3H).

Preparation 188: 1-bromo-2-fluoro-4-methoxy-5-propoxybenzene

1-bromo-2-fluoro-4-methoxy-5-propoxybenzene (13.5 g, 95%) was preparedin an analogous manner to Preparation 172 using5-bromo-4-fluoro-2-methoxyphenol (Preparation 192, 12 g, 109 mmol) and1-iodopropane (18.5 g, 109 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 6.98 (d,J=6.8 Hz, 1H), 6.70 (d, J=9.8 Hz, 1H), 3.93 (t, J=6.8 Hz, 2H), 3.84 (s,3H), 1.81-1.90 (m 2H), 1.04 (t, J=7.6 Hz, 3H).

Preparation 189: 5-bromo-2-methoxy-4-methylphenol

To a mixture of 5-bromo-2-methoxy-4-methylphenyl formate (Preparation190, 19.3 g, 78.58 mmol) in MeOH (100 mL) and water (100 mL) was addedNaOH (4.72 g, 118.1 mmol). The mixture was stirred at about 20° C. forabout 1 h. The mixture was acidified using 1N HCl to pH 3. The mixturewas concentrated and the remaining aqueous phase was extracted withEtOAc (3×150 mL). The combined EtOAc extracts were dried, filtered andconcentrated. The residue was purified by column chromatography (silica)and eluted with pet. ether/EtOAc (100:0 to 80:20) to afford5-bromo-2-methoxy-4-methylphenol (10.25 g, 60% over 2 steps). ¹H NMR(CDCl₃, 400 MHz): δ 7.10 (s, 1H), 6.72 (s, 1H), 5.46 (br s, 1H), 3.87(s, 3H), 2.33 (s, 3H).

Preparation 190: 5-bromo-2-methoxy-4-methylphenyl formate

To a mixture of 5-bromo-2-methoxy-4-methylbenzaldehyde (Preparation 191,18.0 g, 78.58 mmol) in DCM (200 mL) was added m-CPBA (33.9 g, 157.0mmol). The mixture was stirred at about 18° C. for about 16 h. Themixture was filtered and the filtrate was concentrated. The residue waswashed with aqueous sodium metabisulfite solution (1N, 200 mL), aqueousNa₂CO₃ (1N, 100 mL) and water. The residue afforded5-bromo-2-methoxy-4-methylphenyl formate (19.3 g), which was used inPreparation 189.

Preparation 191: 5-bromo-2-methoxy-4-methylbenzaldehyde

To a mixture of 1-bromo-4-methoxy-2-methylbenzene (25.1 g, 125.0 mmol)in TFA (120 mL) was added HMTA (26.3 g, 188 mmol) in portions. Themixture was stirred at about 80° C. for about 12 h. The mixture waspoured into water (500 mL) and stirred at about 20° C. for about 2 h,forming a precipitate. The precipitate was filtered, suspended in waterat about 60° C. for about 20 min, cooled to about 20° C. and filtered.The precipitate was dissolved in EtOAc (300 mL), dried over Na₂SO₄,filtered and concentrated to afford5-bromo-2-methoxy-4-methylbenzaldehyde (18.0 g, 63%). ¹H NMR (CDCl₃, 400MHz): δ 10.34 (s, 1H), 7.95 (s, 1H), 6.88 (s, 1H), 3.92 (s, 3H), 2.45(s, 3H).

Preparation 192: 5-bromo-4-fluoro-2-methoxyphenol

To a solution of 4-fluoro-2-methoxyphenol (5 g, 40 mmol) and Fe powder(98.2 mg, 1.76 mmol) in DCM (230 mL) was added a solution of Br₂ (6.18g, 38.7 mmol) in DCM (20 mL). The solution was stirred for about 16 h atabout 20° C. The mixture was washed with water (3×200 mL) and NaOH (1N).The DCM layer was dried (Na₂SO₄) and concentrated. The residue waspurified by column chromatography (silica) and eluted with pet.ether/EtOAc (100:0 to 90:10) to afford 5-bromo-4-fluoro-2-methoxyphenol(6.0 g, 77%). ¹H NMR (CDCl₃, 400 MHz): δ 7.07 (d, J=6.8 Hz, 1H), 6.68(d, J=9.6 Hz, 1H), 5.47 (s, 1H), 3.87 (s, 3H).

Preparation 193: 2-ethoxy-1,5-difluoro-3-methoxybenzene

To a mixture of 2-ethoxy-3,5-difluorophenol (6.0 g, 34.45 mmol) andiodomethane (Preparation 194, 24.5 g, 172.0 mmol) in MeCN (100 mL) wasadded K₂CO₃ (9.52 g, 68.9 mmol). The mixture was warmed to about 60° C.and stirred for about 5 h. The mixture was cooled to about 20° C.,filtered and concentrated. The residue was dissolved in EtOAc (200 mL).The EtOAc layer was washed with water (80 mL), brine (50 mL), dried overMgSO4, filtered and concentrated to afford2-ethoxy-1,5-difluoro-3-methoxybenzene (5.0 g, 77%), which was used inPreparation 137. ¹H NMR (CDCl₃, 400 MHz): δ 6.43-6.50 (m, 2H), 4.07 (q,J=7.0 Hz, 2H), 3.85 (s, 3H), 1.36 (t, J=7.0 Hz, 3H).

Preparation 194: 2-ethoxy-3,5-difluorophenol

To a mixture of2-(2-ethoxy-3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 195, 13.0 g, 45.76 mmol) in THF (100 mL) was added H₂O₂(30%, 7.78 g, 68.6 mmol) and aqueous NaOH (1M, 48.0 mL, 48.0 mmol) atabout 0° C. The mixture was allowed to warm to about 25° C. for about 2h. The mixture was acidified with 1N HCl to pH 5. Brine (100 mL) wasadded and the mixture was extracted with EtOAc (2×200 mL). The combinedEtOAc extracts were dried over NaSO₄, filtered and concentrated. Theresidue was purified by column chromatography (silica) and eluted withpet. ether/EtOAc (10:1) to afford 2-ethoxy-3,5-difluorophenol (6.0 g,75%). ¹H NMR (CDCl₃, 400 MHz): δ 6.49-6.52 (m, 1H), 6.37-6.43 (m, 1H),5.95 (d, J=1.5 Hz, 1H), 4.18 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H).

Preparation 195:2-(2-ethoxy-3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A combined mixture of 1-bromo-2-ethoxy-3,5-difluorobenzene (Preparation196, 11.0 g, 46.4 mmol), Pin₂B₂ (6.53 g, 51.0 mmol) Pd(dppf)Cl₂ (1.7 g,2.32 mmol) and KOAc (9.11 g, 92.8 mmol) in anhydrous 1,4-dioxane (200mL) was degassed, heated and stirred at about 80° C. for about 24 hunder N₂. The suspension was filtered and the filtrate was concentrated.The residue was purified by column chromatography (silica) and elutedwith pet. ether/EtOAc (100:0 to 70:30) to afford2-(2-ethoxy-3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(13.0 g, 99%). ¹H NMR (CDCl₃, 400 MHz): δ 7.14-7.17 (m, 1H), 6.90-6.95(m, 1H), 4.06 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H), 1.37 (s, 12H).LCMS m/z=285 [MH]⁺.

Preparation 196: 1-bromo-2-ethoxy-3,5-difluorobenzene

To a mixture of 2-bromo-4,6-difluorophenol (10.0 g, 47.85 mmol) andiodoethane (14.9 g, 95.7 mmol) in MeCN (200 mL) was added K₂CO₃ (13.2 g,95.7 mmol). The mixture was warmed to about 60° C. and stirred for about16 h. The mixture was cooled to about 20° C., filtered and the filtrateconcentrated. The residue was dissolved in EtOAc (200 mL). The EtOAclayer was washed with water (80 mL), brine (50 mL), dried over MgSO₄,filtered and concentrated to afford 1-bromo-2-ethoxy-3,5-difluorobenzene(11.0 g, 97%), which was used in Preparation 195. ¹H NMR (CDCl₃, 400MHz): δ 7.09-7.12 (m, 1H), 6.82-6.88 (m, 1H), 4.12 (q, J=7.0 Hz, 2H),1.43 (t, J=7.0 Hz, 3H).

Preparation 197: 4-bromo-1,2-diethoxybenzene

4-bromo-1,2-diethoxybenzene (6.3 g, 97%) was prepared in an analogousmanner to Preparation 172 using 4-bromobenzene-1,2-diol (5.0 g, 26mmol). ¹H NMR (CDCl₃, 400 MHz): δ 6.96-7.01 (m, 2H), 6.71-6.76 (m, 1H),4.06 (dq, J=3.5, 7.0 Hz, 4H), 1.40-1.48 (m, 6H).

Preparation 198: 4-bromo-1-ethoxy-2-methoxybenzene

4-bromo-1-ethoxy-2-methoxybenzene (5.1 g, 98%) was prepared in ananalogous manner to Preparation 172 using 4-bromo-2-methoxyphenol (4.57g, 22.5 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 6.99-7.03 (m, 1H), 6.97-6.99(m, 1H), 6.74 (d, J=8.8 Hz, 1H), 4.07 (q, J=6.9 Hz, 2H), 3.86 (s, 3H),1.46 (t, J=6.9 Hz, 3H). LCMS m/z=231 [MH]⁺.

Preparation 199: 1-bromo-4-ethoxy-2-fluoro-3-methoxybenzene

1-bromo-4-ethoxy-2-fluoro-3-methoxybenzene was prepared as a yellow oil(6.3 g, 99%) in an analogous manner to Preparation 172 using3-bromo-6-ethoxy-2-fluorophenol (Preparation 200, 6 g, 25.5 mmol) andiodomethane (10.9 g, 76.6 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 7.13-7.19(m, 1H), 6.60 (dd, J=2.0, 9.3 Hz, 1H), 4.08 (q, J=7.2 Hz, 2H), 3.93 (d,J=1.0 Hz, 3H), 1.46 (t, J=7.1 Hz, 3H).

Preparation 200: 3-bromo-6-ethoxy-2-fluorophenol

To a solution of2-(3-bromo-6-ethoxy-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 201, 15.2 g, 44.1 mmol) in THF (150 mL) was added H₂O₂(30%, 7.49 g, 66.1 mmol) and aqueous NaOH (1M, 46.3 mL, 46.3 mmol) atabout 0° C. The mixture was allowed to warm to about 25° C. for about1.5 h. The mixture was acidified with 1N HCl to pH 5. Brine (150 mL) wasadded and the mixture was extracted with EtOAc (2×200 mL). The combinedEtOAc extracts were dried over Na₂SO₄, filtered and concentrated toafford 3-bromo-6-ethoxy-2-fluorophenol (10.0 g, 97%). ¹H NMR (CDCl₃, 400MHz): δ 6.99 (dd, J=7.0, 9.0 Hz, 1H), 6.53-6.62 (m, 1H), 4.07-4.20 (m,3H), 1.46 (t, J=7.0 Hz, 3H).

Preparation 201:2-(3-bromo-6-ethoxy-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of 1-bromo-4-ethoxy-2-fluorobenzene (Preparation 202, 11.0g, 50.2 mmol) in THF (250 mL) was added dropwise a solution of LDA (37.7mL, 75.3 mmol, 2 M in THF) at about −78° C. The solution was stirred atabout −78° C. for about 1 h, PinBO-Pr (14.0 g, 75.3 mmol) was addeddropwise. After stirring at about −78° C. for about 2 h, the solutionwas quenched with aqueous NH₄Cl (1 M, 100 mL) and extracted with MTBE(3×300 mL). The combined MTBE extracts were washed with brine (200 mL),dried over Na₂SO₄, and concentrated. The residue was purified by columnchromatography (silica) and eluted with pet. ether/EtOAc (10:1) toafford2-(3-bromo-6-ethoxy-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(15.2 g, 88%). ¹H NMR (CDCl₃, 400 MHz): δ 7.43 (t, J=8.6 Hz, 1H), 6.51(d, J=8.8 Hz, 1H), 3.99 (q, J=6.9 Hz, 2H), 1.35-1.45 (m, 16H).

Preparation 202: 1-bromo-4-ethoxy-2-fluorobenzene

1-bromo-4-ethoxy-2-fluorobenzene (11 g, 96%) was prepared in ananalogous manner to Preparation 172 using 4-bromo-2-methoxyphenol (10 g,52 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 7.33-7.45 (m, 1H), 6.69 (dd, J=2.9,10.8 Hz, 1H), 6.60 (ddd, J=1.0, 2.9, 8.8 Hz, 1H), 4.00 (q, J=7.2 Hz,2H), 1.42 (t, J=6.9 Hz, 3H).

Preparation 203: (4-bromo-2-methoxyphenyl)(methyl)sulfane

To a solution of dimethyl disulfide (35 g, 371 mmol) and isopentylnitrite (57.9 g, 495 mmol) in THF (600 mL) was added4-bromo-2-methoxybenzenamine (50 g, 247.46 mmol) slowly. The mixture wasstirred at about 70° C. for about 3 h. The reaction mixture wasconcentrated. The residue was purified by column chromatography (silica)and eluted with pet. ether/EtOAc (100:0 to 90:10) to afford(4-bromo-2-methoxyphenyl)(methyl)sulfane (50 g, 87%). ¹H NMR (CDCl₃, 400MHz): δ 7.07-7.12 (m, 1H), 6.99-7.03 (m, 1H), 6.96 (d, J=2.0 Hz, 1H),3.90 (s, 3H), 2.42 (s, 3H). LCMS m/z=233.0 [MH]⁺.

Preparation 204: (4-bromo-2-ethoxyphenyl)(methyl)sulfane

(4-bromo-2-ethoxyphenyl)(methyl)sulfane (35.0 g, 83%) was prepared in ananalogous manner to Preparation 172 using 5-bromo-2-(methylthio)phenol(Preparation 20, 16 g, 73 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 7.05-7.09(m, 1H), 6.97-7.01 (m, 1H), 6.94 (d, J=2.0 Hz, 1H), 4.09 (q, J=7.1 Hz,2H), 2.41 (s, 3H), 1.47 (t, J=7.0 Hz, 3H).

Preparation 205: (4-bromo-2-(cyclopentyloxy)phenyl)(methyl)sulfane

(4-bromo-2-(cyclopentyloxy)phenyl)(methyl)sulfane (6.0 g, 92%) wasprepared in an analogous manner to Preparation 153 using5-bromo-2-(methylthio)phenol (5 g, 22.8 mmol) and cyclopentanol (2.36 g,27.4 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 7.05 (dd, J=2.0, 8.3 Hz, 1H),6.93-6.98 (m, 2H), 4.80-4.84 (m, 1H), 2.38 (s, 3H), 1.79-1.95 (m, 6H),1.60-1.68 (m, 2H).

Preparation 206: 5-bromo-2-(methylthio)phenol

To a solution of (4-bromo-2-methoxyphenyl)(methyl)sulfane (19.0 g, 81.5mmol) in DCM (300 mL) at about −78° C. was added BBr₃ (179 mL, 179 mmol,1 M in DCM) dropwise under N₂ atmosphere. The reaction mixture wasallowed to warm to about 20° C. and stirred for about 2 h. The mixturewas quenched with MeOH at about 0° C. and concentrated. The residue waspurified by column chromatography (silica) and eluted with pet.ether/EtOAc (100:0 to 70:30) to afford 5-bromo-2-(methylthio)phenol(16.3 g, 91%). ¹H NMR (CDCl₃, 400 MHz): δ 7.35 (d, J=8.3 Hz, 1H), 7.17(d, J=2.2 Hz, 1H), 7.03 (dd, J=2.2, 8.3 Hz, 1H), 6.67 (br s, 1H), 2.32(s, 3H).

Preparation 207: 6-bromo-2-(cyclopentyloxy)-3-methoxybenzonitrile

A mixture of 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde oxime(Preparation 208, 7 g, 22.3 mmol), TFAA (7.16 g, 33.45 mmol) and Et₃N(6.76 g, 66.9 mmol) in DCM (100 mL) was stirred at about 20° C. forabout 16 h. Water (200 mL) was added to the mixture and extracted withDCM (2×200 mL). The combined DCM extracts were washed with brine (200mL), dried and concentrated. The residue was purified by columnchromatography (silica) and eluted with pet. ether/EtOAc (10:1) toafford 6-bromo-2-(cyclopentyloxy)-3-methoxybenzonitrile (1.6 g, 24%). ¹HNMR (CDCl₃, 400 MHz): δ 7.26-7.30 (m, 1H), 6.96 (d, J=8.8 Hz, 1H),5.11-5.17 (m, 1H), 3.87 (s, 3H), 1.89-2.02 (m, 4H), 1.70-1.80 (m, 2H),1.59-1.68 (m, 2H).

Preparation 208: 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde oxime

To a solution of 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde(Preparation 209, 6.8 g, 22.7 mmol) in EtOH (100 mL) was added NaHCO₃(3.8 g, 45.4 mmol) and NH₂OH.HCl (2.35 g, 34 mmol). The mixture wasstirred at about 20° C. for about 2 h. The reaction mixture wasconcentrated to afford 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehydeoxime (7 g), which was used in Preparation 207.

Preparation 209: 6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde

6-bromo-2-(cyclopentyloxy)-3-methoxybenzaldehyde (6.8 g, 90%) wasprepared in an analogous manner to Preparation 172 using6-bromo-2-hydroxy-3-methoxybenzaldehyde (Preparation 165, 6 g, 30 mmol)and bromocyclopentane (4.26 g, 28.6 mmol) at about 60° C. for about 3 h.¹H NMR (CDCl₃, 400 MHz): δ 10.31-10.38 (m, 1H), 7.31 (d, J=8.8 Hz, 1H),6.94 (d, J=8.8 Hz, 1H), 4.95-5.01 (m, 1H), 3.87 (s, 3H), 1.70-1.93 (m,7H), 1.62 (d, J=5.4 Hz, 2H). LCMS m/z=323 [M+Na]⁺.

Preparation 210: 1-bromo-2,4-dimethoxy-3-propoxybenzene

1-bromo-2,4-dimethoxy-3-propoxybenzene (10 g, 85%) was prepared in ananalogous manner to Preparation 172 using 3-bromo-2,6-dimethoxyphenol(Preparation 211, 10 g, 43 mmol) and 1-iodopropane (14.6 g, 86 mmol). ¹HNMR (CDCl₃, 400 MHz): δ 7.17-7.22 (m, 1H), 6.58 (d, J=8.8 Hz, 1H),3.95-3.99 (m, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 1.73-1.85 (m, 2H),1.01-1.07 (m, 4H). LCMS m/z=276 [MH]⁺.

Preparation 211: 3-bromo-2,6-dimethoxyphenol

To a stirring solution of 2,6-dimethoxyphenol (1 g, 6.5 mmol) in CCl₄(35 mL) at about −10° C. was added Br₂ (1.04 g, 6.5 mmol) and stirredfor about 2 h. The reaction mixture was diluted with CCl₄ (20 mL),washed with water (3×60 mL) and the CCl₄ layer was washed with brine,dried over Na₂SO₄ and concentrated. The residue was purified by columnchromatography (silica) and eluted with pet. ether/EtOAc (100:0 to80:20) to afford 3-bromo-2,6-dimethoxyphenol (1.46 g, 97%). ¹H NMR(CDCl₃, 400 MHz): δ 7.02 (d, J=8.8 Hz, 1H), 6.57 (d, J=8.8 Hz, 1H), 5.66(s, 1H), 3.93 (s, 3H), 3.89 (s, 3H).

Preparation 212: 6-iodo-3-methoxy-2-propoxypyridine

6-iodo-3-methoxy-2-propoxypyridine was (11 g, 95%) prepared in ananalogous manner to Preparation 172 using 6-iodo-2-propoxypyridin-3-ol(Preparation 213, 11 g, 39 mmol) and 1-iodomethane (57 g, 402 mmol) atabout 15° C. for about 6 h. ¹H NMR (CDCl₃, 400 MHz): δ 7.24 (d, J=8.0Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 4.25 (t, J=6.8 Hz, 2H), 3.83 (s, 3H),1.73-1.90 (m, 2H), 1.04 (t, J=7.5 Hz, 3H). LCMS m/z=293 [MH]⁺.

Preparation 213: 6-iodo-2-propoxypyridin-3-ol

Sodium propan-1-olate (21.8 g, 265 mmol) was added to2-bromo-6-iodopyridin-3-ol (Preparation 214, 26.5 g, 88.4 mmol) in DMF(200 mL), and the reaction mixture was stirred for about 16 h at about110° C. under N₂. After cooling to about 20° C., the reaction mixturewas partitioned between brine (200 mL) and EtOAc (250 mL). The aqueouslayer was extracted with EtOAc (200 mL). The combined EtOAc extractswere dried (Na₂SO₄) and concentrated. The residue was purified by columnchromatography (silica) and eluted with pet. ether/EtOAc (100:0 to80:20) to afford 6-iodo-2-propoxypyridin-3-ol (11.2 g, 45%). ¹H NMR(CDCl₃, 400 MHz): δ 7.17 (d, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 5.47(s, 1H), 4.31 (dt, J=0.9, 6.7 Hz, 2H), 1.74-1.86 (m, 2H), 0.98-1.05 (m,3H).

Preparation 214: 2-bromo-6-iodopyridin-3-ol

To a solution of 2-bromo-3-hydroxy pyridine (20.0 g, 114.95 mmol) inwater (250 mL) was added K₂CO₃ (31.8 g, 230 mmol) and 12 (29.2 g, 115mmol). The mixture was stirred at about 20° C. for about 5 h. Themixture was cooled to 0° C. and treated with concentrated HCl. Theprecipitate was filtered to afford 2-bromo-6-iodopyridin-3-ol (30 g,87%). ¹H NMR (DMSO-d₆, 400 MHz): δ 11.10 (br s, 1H), 7.62 (d, J=8.1 Hz,1H), 7.03 (d, J=8.3 Hz, 1H). LCMS m/z=299 [MH]⁺.

Preparation 215: 5-bromo-2-methoxy-3-propoxypyridine

To a solution of 2-methoxy-3-propoxypyridine (Preparation 216, 5.68 g,34 mmol) dissolved in DCM (60 mL) was added HOAc (2.04 g, 34 mmol). Tothe mixture, NBS (6.35 g, 35.7 mmol) was added in portions whilestirring. The mixture was stirred at about 12° C. for about 16 h. Themixture was concentrated. The residue was diluted with water (200 mL)and extracted with EtOAc (2×100 mL) The combined EtOAc extracts weredried and concentrated. The residue was purified by columnchromatography (silica) and eluted with pet. ether/EtOAc (100:0 to85:15) to afford a mixture of 6-bromo-2-methoxy-3-propoxypyridine and5-bromo-2-methoxy-3-propoxypyridine. The mixture was chilled to about−10° C. overnight. A precipitate formed which was separated from the oilby centrifugation (3×5 min @ 3000 rpm) to afford5-bromo-2-methoxy-3-propoxypyridine (3 g, 53%). ¹H NMR (CDCl₃, 400 MHz):δ 7.76 (d, J=2.0 Hz, 1H), 7.13 (d, J=2.0 Hz, 1H), 3.98 (s, 3H), 3.95 (t,J=6.8 Hz, 2H), 1.85-1.94 (m, 2H), 1.05 (t, J=7.5 Hz, 3H).

Preparation 216: 2-methoxy-3-propoxypyridine

2-methoxy-3-propoxypyridine (5.7 g, 85%) was prepared in an analogousmanner to Preparation 172 using 2-methoxypyridin-3-ol (5 g, 40 mmol) and1-iodopropane (13.6 g, 80 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 7.73 (dd,J=1.5, 4.9 Hz, 1H), 7.05 (dd, J=1.5, 7.82 Hz, 1H), 6.83 (dd, J=5.0, 7.7Hz, 1H), 4.02 (s, 3H), 3.97 (t, J=6.9 Hz, 2H), 1.86-1.93 (m, 2H), 1.05(t, J=7.5 Hz, 3H).

Preparation 217: 2-bromo-5-methoxy-4-propoxypyridine

To a solution of 2-bromo-4-iodo-5-methoxypyridine (Preparation 218, 4.0g, 13 mmol) in DMF (30 mL) was added NaH (765 mg, 19.1 mmol, 60%) and1-propanol (1.53 g, 25.5 mmol) in DMF (25 mL) at about 20° C. Themixture was heated to about 60° C. for about 1 h. The solution wasquenched with aqueous NH₄Cl (1 M, 30 mL) and extracted with EtOAc (3×100mL). The combined EtOAc extracts were washed with brine (100 mL), driedover Na₂SO₄ and concentrated. The residue was purified by columnchromatography (silica) and eluted with pet. ether/EtOAc (100:0 to89:11) to afford 2-bromo-5-methoxy-4-propoxypyridine (2 g, 64%). ¹H NMR(CDCl₃, 400 MHz): δ 7.84 (s, 1H), 6.91 (s, 1H), 4.00 (t, J=6.9 Hz, 2H),3.90 (s, 3H), 1.83-1.92 (m, 2H), 1.05 (t, J=7.3 Hz, 3H). LCMS m/z=247.8[MH]⁺.

Preparation 218: 2-bromo-4-iodo-5-methoxypyridine

Sodium hydride (1.27 g, 31.8 mmol, 60%) was suspended in MeOH (2.55 g,79.5 mmol) and DMF (80 mL) at about 25° C. The mixture was added to asolution of 2-bromo-5-fluoro-4-iodopyridine (Preparation 219, 8 g, 26.50mmol) in DMF (10 mL) at about 0° C. The mixture was stirred at about 0°C. for about 1 h. The solution was quenched with aqueous NH₄Cl (1 M, 60mL) and extracted with MBTE (3×200 mL). The combined MTBE extracts werewashed with brine (100 mL), dried over Na₂SO₄, and concentrated. Theresidue was purified by column chromatography (silica) and eluted withpet. ether/EtOAc (100:0 to 90:10) to afford2-bromo-4-iodo-5-methoxypyridine (4 g, 48.1%). ¹H NMR (CDCl₃, 400 MHz):δ 7.88 (s, 1H), 7.85 (s, 1H), 3.97 (s, 3H).

Preparation 219: 2-bromo-5-fluoro-4-iodopyridine

A solution of 2-bromo-5-fluoropyridine (24.6 g, 140 mmol) in THF (300mL) was cooled to about −78° C. LDA (2 M in THF, 90.9 mL, 182 mmol) wasadded dropwise and the mixture was stirred for about 20 min. To themixture was added a solution of iodine (49.7 g, 196 mmol) in THF (100mL) dropwise. The reaction mixture was warmed to about 0° C. and stirredfor about 30 min. The reaction was quenched with 10% aq. Na₂S2O₃solution and was extracted with EtOAc (3×500 mL). The combined EtOAcextracts were washed with brine (500 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by column chromatograph(silica) and eluted with pet. ether/EtOAc (10:1) to afford2-bromo-5-fluoro-4-iodopyridine (50 g, 67% purity). The material wasfurther purified by preparative HPLC (Column: Phenomenex Synergi Max-RP150 mm×50 mm, 10μ; Mobile Phase: [water (0.225% HCO₂H)-ACN]; B %:30%-60%, 25 min. Flow rate 120 mL/min.) to afford2-bromo-5-fluoro-4-iodopyridine (16.8 g, 40%). ¹H NMR (CDCl₃, 400 MHz):δ 8.15 (s, 1H), 7.92 (s, 1H). LCMS m/z=303 [MH]⁺.

Preparation 220: 3-fluoro-2-iodo-5-methoxy-6-propoxypyridine

To a solution of 5-fluoro-3-methoxy-2-propoxypyridine (Preparation 221,2.80 g, 15.1 mmol) in EtOH (50 mL) was added Ag₂SO₄ (7.07 g, 22.7 mmol)and 12 (5.76 g, 22.7 mmol). The reaction mixture was stirred at about10° C. for about 16 h. The mixture was and the solution was partitionedbetween EtOAc (3×100 mL) and water (100 mL). The EtOAc extracts weredried with Na₂SO₄, filtered and concentrated to afford3-fluoro-2-iodo-5-methoxy-6-propoxypyridine (4.38 g, 93%). ¹H NMR(CDCl₃, 400 MHz): δ 7.58-7.74 (m, 1H), 4.30 (t, J=6.7 Hz, 2H), 3.92 (s,3H), 1.75-1.91 (m, 2H), 1.05 (t, J=7.3 Hz, 3H). LCMS m/z=311 [MH]⁺.

Preparation 221: 5-fluoro-3-methoxy-2-propoxypyridine

A mixture of tBuXPhos-Pd-G3 (CAS 14447963-75-8, 443 mg, 0.557 mmol),PrOH (803 mg, 13.4 mmol), 2-chloro-5-fluoro-3-methoxypyridine(Preparation 222, 1800 mg, 11.14 mmol) and Cs₂CO₃ (7260 mg, 22.3 mmol)was dissolved in PrOH (40 mL) under a N₂. The mixture was heated atabout 90° C. for about 16 h. The mixture was dried and concentrated. Theresidue was purified by by column chromatography (silica) and elutedwith pet. ether/EtOAc (100:0 to 90:10) to afford5-fluoro-3-methoxy-2-propoxypyridine (1280 mg, 77%). ¹H NMR (CDCl₃, 400MHz): δ 7.57 (d, J=2.5 Hz, 1H), 6.87 (dd, J=2.7, 9.3 Hz, 1H), 4.31 (t,J=7.0 Hz, 2H), 3.87 (s, 3H), 1.77-1.93 (m, 2H), 0.98-1.08 (m, 3H). LCMSm/z=185 [MH]⁺.

Preparation 222: 2-chloro-5-fluoro-3-methoxypyridine

2-chloro-5-fluoro-3-methoxypyridine (1.8 g, 72%) was prepared in ananalogous manner to Preparation 153 using 2-chloro-5-fluoropyridin-3-ol(2.3 g, 16 mmol) and methanol (5 g, 156 mmol). ¹H NMR (CDCl₃, 400 MHz):δ 7.89 (d, J=2.70 Hz, 1H), 7.00 (dd, J=2.5, 9.1 Hz, 1H), 3.93 (s, 3H).

Preparation 223: 4-bromo-1-(difluoromethoxy)-2-propoxybenzene

Powdered KOH (1.34 g, 23.8 mmol) was added to a stirring solution of4-bromo-2-propoxyphenol (Preparation 224, 5.5 g, 23.8 mmol) in NMP (150mL) at about 15° C. under N₂. The mixture was heated at about 50° C. forabout 45 min then cooled to about 15° C. Difluorochloromethane wasbubbled through the reaction mixture (approximately 20 min) untilsaturation and the mixture was stirred for an additional 20 min.Potassium hydroxide (2.68 g in 3 mL of water) was added dropwise,maintaining the temperature below 33° C. The mixture was stirred for anadditional 40 min. Additional potassium hydroxide (1.34 g, in 3 mL ofwater) was added dropwise and the mixture was stirred for 1 h. N₂ wasbubbled through the reaction and water was added. The pH of theresulting mixture was adjusted to 8 by the addition of potassiumhydroxide (aqueous) and the mixture was extracted using MTBE (2×100 mL).The combined MBTE extracts were washed with water (50 mL), brine (3×100mL), dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by column chromatography (silica) and eluted with pet.ether/EtOAc (100:0 to 90:10) to afford4-bromo-1-(difluoromethoxy)-2-propoxybenzene (4.8 g, 72%). ¹H NMR(CDCl₃, 400 MHz): δ 7.09 (d, J=1.3 Hz, 1H), 7.03-7.06 (m, 2H), 6.33-6.74(m, 1H), 3.93-4.01 (m, 2H), 1.80-1.92 (m, 2H), 1.06 (t, J=7.4 Hz, 3H).

Preparation 224: 4-bromo-2-propoxyphenol

To a solution of 4-bromo-2-propoxyphenyl formate (Preparation 225, 10.9g, 42 mmol) in MeOH (75 mL) and water (75 mL) was added NaOH (4200 mg,105 mmol). The mixture was stirred at about 10° C. for about 1 h. Themixture was allowed to stand overnight. The mixture was acidified by HCl(1N) to pH 3. The mixture was concentrated and filtered. The filter cakewas washed with water (20 mL). The cake was dissolved in MTBE (200 mL)and EtOAc (50 mL). The combined MTBE and EtOAc extracts were dried overNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography (silica) and eluted with pet. ether/EtOAc (100:0 to75:25) to afford 4-bromo-2-propoxyphenol (6.11 g, 63%). ¹H NMR (CDCl₃,400 MHz): δ 6.94-7.06 (m, 2H), 6.81 (d, J=8.5 Hz, 1H), 3.99 (t, J=6.8Hz, 2H), 1.79-1.95 (m, 2H), 1.06 (t, J=7.5 Hz, 3H).

Preparation 225: 4-bromo-2-propoxyphenyl formate

To a solution of 4-bromo-2-propoxybenzaldehyde (Preparation 226, 10.2 g,42 mmol) dissolved in DCM (150 mL) was added m-CPBA (18.1 g, 84 mmol).The mixture was stirred at about 18° C. for about 16 h, then allowed tostand over the weekend. The mixture was filtered and concentrated toafford 4-bromo-2-propoxyphenyl formate (10.9 g), which was used inPreparation 224. LCMS m/z=248 [MH]⁺.

Preparation 226: 4-bromo-2-propoxybenzaldehyde

4-bromo-2-propoxybenzaldehyde (11.5 g, 95%) was prepared in an analogousmanner to Preparation 172 using 4-bromo-2-hydroxybenzaldehyde (10 g, 50mmol) and 1-iodopropane (11 g, 65 mmol). ¹H NMR (CDCl₃, 400 MHz): δ10.45 (d, J=0.7 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.11-7.22 (m, 2H), 4.04(t, J=6.5 Hz, 2H), 1.80-2.02 (m, 2H), 1.09 (t, J=7.3 Hz, 3H).

Preparation 227: ((2-bromoallyl)oxy)(tert-butyl)dimethylsilane

Five reactions were carried out in parallel. To a solution of2-bromoprop-2-en-1-ol (Preparation 60, 150 g, 1.10 mol) and imidazole(Preparation 228, 74.6 g, 0.985 mol) in DMF (900 mL) was added TBS-Cl(140 g, 0.93 mol) in portions at about 30° C. Then the mixture wasstirred at about 35° C. for 1 h. The mixture was poured into water (5.0L). The combined mixtures were extracted with MTBE (3×2.5 L). Theorganic layer was washed with brine (2.0 L), dried over Na₂SO₄ andconcentrated to afford ((2-bromoallyl)oxy)(tert-butyl)dimethylsilane(1250 g, 92%). ¹H NMR (CDCl₃, 400 MHz): δ 5.96 (d, J=1.8 Hz, 1H), 5.54(d, J=1.8 Hz, 1H), 4.22 (t, J=1.5 Hz, 2H), 0.89-0.97 (m, 9H), 0.11 (s,6H).

Preparation 228: 2-bromoprop-2-en-1-ol

Five reactions were carried out in parallel: To a solution of2,3-dibromoprop-1-ene (300 g, 1.50 mol) in DMF (900 mL) was added KOAc(221 g, 2.25 mol) in portions with stirring at about 20° C. The mixturewas stirred at about 20° C. for about 12 h. A solution of LiOH (126 g,3.01 mol) in MeOH (900 mL) and H₂O (300 mL) was added dropwise to theabove mixture with stirring at about 20° C. The mixture was stirred atabout 20° C. for about 1 h. The mixture was concentrated and poured intoice-water (2.0 L). The mixture was extracted with EtOAc (3×1.5 L). TheEtOAc extracts were washed with brine (1.0 L), dried over Na₂SO₄ andconcentrated to afford 2-bromoprop-2-en-1-ol (750 g, 72%). ¹H NMR(CDCl₃, 400 MHz): δ 5.87-6.02 (m, 1H), 5.45-5.62 (m, 1H), 4.17 (s, 2H),3.70 (br s, 1H).

Preparation 229: ((3-bromobut-3-en-1-yl)oxy)(tert-butyl)dimethylsilane

To a mixture of 3-bromobut-3-en-1-ol (CAS 76334-36-6, 10.0 g, 66.2 mmol)in anhydrous DCM (65 mL) was added imidazole (5.41 g, 79.5 mmol) andTBS-Cl (9.98 g, 66.2 mmol). The mixture was stirred at about 18° C. forabout 16 h. The reaction was poured into ice water and extracted withEtOAc (2×200 mL). The combined EtOAc extracts were washed with brine,dried over Na₂SO₄ and filtered. The filtrate was concentrated. Theresidue was purified by column chromatography (silica) and eluted withpet. ether to afford((3-bromobut-3-en-1-yl)oxy)(tert-butyl)dimethylsilane (16.0 g, 91%). ¹HNMR (CDCl₃, 400 MHz): δ 5.64 (s, 1H), 5.46 (d, J=1.6 Hz, 1H), 3.80 (t,J=6.4 Hz, 2H), 2.63 (t, J=6.2 Hz, 2H), 0.90 (s, 9H), −0.08 (s, 6H).

Preparation 230:4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dichloropyrimidine

To a solution of 2,6-dichloropyrimidin-4-yl)methanol (Preparation 231,3.5 g, 19.55 mmol) and imidazole (1.6 g, 23.5 mmol) in DMF (60 mL) wasadded TBS-Cl (3.24 g, 22.4 mol) in portions at about 0° C. The mixturewas stirred at about 0° C. for about 2 h. The mixture was poured intoice water (50 mL) and extracted with EtOAc (3×50 mL). The combined EtOAcextracts were washed with brine (2×30 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by column chromatography(silica) and eluted with pet. ether/EtOAc (100:0 to 90:10) to afford4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dichloropyrimidine (3.1 g,54%). ¹H NMR (CDCl₃, 400 MHz): δ 7.48-7.57 (m, 1H), 4.72-4.82 (m, 2H),0.93-1.03 (m, 9H), 0.14 (s, 6H). LCMS m/z=293 [MH]⁺.

Preparation 231: 2,6-dichloropyrimidin-4-yl)methanol

2,6-Dichloropyrimidine-4-carbonyl chloride (Preparation 232, 10 g, 47.3mmol) was dissolved in a mixture of MeCN (60 mL) and THF (70 mL). Themixture was cooled to about −78° C. and treated with a solution of NaBH₄(3.58 g, 94.6 mmol) in DMF (30 mL) dropwise. The mixture was stirred atabout −78° C. for about 2 h and diluted with aqueous HCl solution (1 M,10 mL). The mixture was diluted with saturated aqueous NaHCO₃ andextracted with EtOAc (2×100 mL). The combined EtOAc extracts were driedover MgSO₄, filtered and concentrated to afford2,6-dichloropyrimidin-4-yl)methanol (8 g, 95%), which was used inPreparation 230. ¹H NMR (CDCl₃, 400 MHz): δ 7.51 (s, 1H), 4.78 (s, 2H).

Preparation 232: 2,6-dichloropyrimidine-4-carbonyl chloride

A solution of 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid(50 g, 0.32 mol) and PCI₅ (220 g, 1.06 mol) in POCl₃ (250 mL) was heatedto reflux (120° C.) for about 16 h. The resulting mixture wasconcentrated and distilled under reduced pressure (120° C., 10 mm Hg) toafford 2,6-dichloropyrimidine-4-carbonyl chloride (21 g, 31%), which wasused in Preparation 231.

Preparation 233: 4-methoxy-3-propoxybenzimidamide

Ethyl 4-methoxy-3-propoxybenzimidate (Preparation 234, 37.6 g, 158.45mmol) was dissolved in EtOH (226 mL). Ammonia in methanol (226 mL) wasadded to the reaction mixture. The reaction mixture was stirred at about28° C. for about 24 h. After concentration, MTBE (150 mL) was pouredinto the residue, stirred for 1 h, and filtered and concentrated toafford 4-methoxy-3-propoxybenzimidamide (33.8 g, 100%). ¹H NMR (CD₃OD,400 MHz): δ 7.46 (dd, J=2.2, 8.6 Hz, 1H), 7.36 (d, J=2.2 Hz, 1H), 7.14(d, J=8.6 Hz, 1H), 4.04 (t, J=6.5 Hz, 2H), 3.93 (s, 3H), 1.81-1.90 (m,2H), 1.07 (t, J=7.6 Hz, 3H). LCMS m/z=209 [MH]⁺.

Preparation 234: ethyl 4-methoxy-3-propoxybenzimidate

Acetyl chloride (69.0 g, 879 mmol) was added dropwise to a solution of4-methoxy-3-propoxybenzonitrile (Preparation 235, 21.0 g, 110 mmol) indry EtOH (60.7 g, 1320 mmol), which was stirred at about 30° C. forabout 12 h. The mixture was concentrated and to the residue was addedMTBE (150 mL). The mixture was stirred for about 1 h and filtered toafford ethyl 4-methoxy-3-propoxybenzimidate (26.1 g, 100%). ¹H NMR(CDCl₃, 400 MHz): δ 12.28 (br s, 1H), 11.56 (br s, 1H), 8.01 (d, J=2.2Hz, 1H), 7.98 (dd, J=2.2, 8.6 Hz, 1H), 7.0 (d, J=8.6 Hz, 1H), 4.91 (q,J=7.0 Hz, 2H), 4.21 (t, J=6.6 Hz, 2H), 3.96 (s, 3H), 1.85-1.96 (m, 2H),1.61 (t, J=7.0 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H). LCMS m/z=238 [MH]⁺.

Preparation 235: 4-methoxy-3-propoxybenzonitrile

4-methoxy-3-propoxybenzonitrile (32.10 g, 100%) was prepared in ananalogous manner to Preparation 172 using3-hydroxy-4-methoxybenzonitrile (25 g, 170 mmol) and 1-iodopropane (57g, 335 mmol). ¹H NMR (CDCl₃, 400 MHz): δ 7.25-7.29 (m, 1H), 7.08 (d,J=2.0 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 3.99 (t, J=6.9 Hz, 2H), 3.92 (s,3H), 1.84-1.93 (m, 2H), 1.03-1.09 (m, 3H). LCMS m/z=191 [MH]⁺.

Preparation 236: 3-((tert-butyldimethylsilyl)oxy)propan-1-ol

Propane-1,3-diol (20 g, 260 mmol), tert-butylchlorodimethylsilane (47.5g, 315 mmol), Et₃N (76.0 mL, 526 mmol) and DMAP (1.610 g, 13.1 mmol)were suspended in DCM (300 mL). The mixture was stirred at about 18° C.overnight. The reaction mixture was partitioned between DCM (3×300 mL)and water (300 mL). The combined DCM extracts were concentrated. Theresidue was purified by column chromatography (silica) and eluted withpet. ether/EtOAc (100:0 to 97:3) to afford3-((tert-butyldimethylsilyl)oxy)propan-1-ol (50 g, 100%), which was usedin Preparation 158.

Preparation 237: 1-(6-bromopyridin-2-yl)-2-hydroxyethan-1-one

Step 1: A solution of 1-(6-bromopyridin-2-yl)ethanone (CAS 49669-13-8,5.0 g, 25.0 mmol) in AcOH (12 mL) was heated to about 70° C. Bromine(1.4 mL, 27.5 mmol) was added dropwise over 30 min. The solution wasstirred at about 70° C. for about 19 h. The solution was cooled EtOAc(50 mL) and hexanes (50 mL) were added. The precipitate was filtered andwashed with heptane (2×50 mL). The combined filtrates were washed withbrine (30 mL), dried over MgSO4, filtered, and concentrated to give a2-bromo-1-(6-bromopyridin-2-yl)ethan-1-one (6.85 g), which was useddirectly in the next step.

Step 2: To a solution of 2-bromo-1-(6-bromopyridin-2-yl)ethanone (6.74g) in DMF (30 mL) was added sodium nitrite (2.00 g). The solution wasstirred at about 20° C. for about 22 h. The reaction was diluted withEtOAc (100 mL) and washed with water (100 mL). The water layersextracted with EtOAc. The combined EtOAc extracts were washed with brine(20 mL), dried with MgSO₄, filtered and concentrated. The residue waspurified by column chromatography (silica) and eluted with heptane/EtOAc(90:10 to 70:30) to afford 1-(6-bromopyridin-2-yl)-2-hydroxyethan-1-one(977 mg), which was used in Preparation 88. ¹H NMR (CDCl₃, 400 MHz): δ7.99-8.11 (m, 1H), 7.68-7.83 (m, 2H), 5.08 (d, J=5.1 Hz, 2H).

Example 1: 4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 1

4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (Example 32,500 mg, 1.67 mmol) was further purified by preparative SFC (Prep SFCMethod A) to afford4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol, enantiomer1 (233 mg, 46%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (d, J=2.8 Hz, 2H),8.43 (d, J=2.0 Hz, 1H), 7.95 (t, J=2.0 Hz, 1H), 7.25-7.29 (m, 1H), 7.06(d, J=8.4 Hz, 2H), 4.28 (t, J=4.28 Hz, 1H), 3.84-3.88 (m, 4H), 3.80 (s,3H), 3.46-3.54 (m, 1H), 1.28-1.34 (m, 1H), 1.12-1.18 (m, 1H). LCMSm/z=300 [MH]⁺;

RT [Analytical SFC Method A]=5.20 min.

Example 2:(S)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example33, 2.3 g, 7.3 mmol) was further purified by preparative SFC (Prep SFCMethod B). The solids were recrystallized from EtOAc (442 mg in 2 mL) toafford 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 1 (253 mg, 11%) as a crystalline solid. ¹H NMR (DMSO-d₆, 400MHz): δ 8.70 (d, J=2.3 Hz, 1H), 8.68 (s, 1H), 8.42 (d, J=1.6 Hz, 1H),7.92-7.94 (m, 1H), 7.23-7.29 (m, 2H), 7.06 (d, J=8.2 Hz, 1H), 4.28 (t,J=8.2 Hz, 1H), 4.13 (q, J=6.8 Hz, 2H), 3.86 (t, J=9.0 Hz, 1H), 3.80 (s,3H), 3.45-3.55 (m, 1H), 1.28-1.39 (m, 4H), 1.10-1.20 (m, 1H). LCMSm/z=314 [MH]⁺; RT [Analytical SFC Method B]=6.59 min. [α]²⁰ _(D) +19.5(c=0.3, EtOH).

Example 3:(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

Further elution of the preparative SFC column (Prep SFC Method B)described in Example 2 provided enantiomer 2 that was recrystallizationfrom EtOAc to afford (R)4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (610mg, 27%) as a crystalline solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.70 (d,J=2.3 Hz, 1H), 8.68 (s, 1H), 8.42 (d, J=1.6 Hz, 1H), 7.92-7.94 (m, 1H),7.23-7.29 (m, 2H), 7.06 (d, J=8.2 Hz, 1H), 4.28 (t, J=8.2 Hz, 1H), 4.13(q, J=6.8 Hz, 2H), 3.86 (t, J=9.0 Hz, 1H), 3.80 (s, 3H), 3.45-3.55 (m,1H), 1.28-1.39 (m, 4H), 1.10-1.20 (m, 1H). LCMS m/z=314 [MH]⁺, RT[Analytical SFC Method B]=7.07 min. [α]²⁰ _(D) −22.5 (c=0.2, EtOH).

Example 4:(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

Method A:

To a mixture of(R)-(3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronicacid (Preparation 6, 55 g, 120 mmol) in IPA (247 mL) was added 5 Mhydrogen chloride in IPA (37 mL, 185 mmol) at about 20° C. The mixturewas stirred for about 3 h and concentrated. The residue was diluted withEtOAc (500 mL) and 1N HCl (500 mL) was added. The layers were separatedand the EtOAc layer was extracted with 0.5 N HCl (2×200 mL). The aqueousextracts were combined with the separated acidic aqueous layer andwashed with EtOAc (3×250 mL). The combined acidic aqueous layers weretreated with K₃PO₄ to pH 5-6. The mixture was extracted with EtOAc(1×500 mL, 2×200 mL). The combined EtOAc extracts were washed withbrine, dried over Na₂SO₄, filtered and concentrated to afford(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(34.5 g, 88%). This was further purified by preparative SFC (Prep SFCMethod C) to afford 29 g as a crude product. The crude product wasdissolved in methanol (250 mL) and water (50 mL) and stirred at 20° C.for about 30 min before concentrating. The concentrated solution waspartitioned between brine and EtOAc. The aqueous layer was separated andextracted with EtOAc. The EtOAc extracts were combined with the separateEtOAc layer and were washed with brine, dried over Na₂SO₄ andconcentrated. The residue was dissolved in degassed EtOAc (200 mL) anddegassed heptane (100 mL) was added slowly. Heptane was added until aprecipitate was observed and and the resulting mixture was stirredovernight under N₂. The solid was filtered to afford 8.08 g of product.The filtrate was concentrated and the residue dissolved in EtOAc (50mL). Heptane (25 mL) was slowly added and the mixture stirred overnightopen to air. The solid was filtered to afford a second batch (6.16 g).This was repeated a second time to afford 3.0 g. The filtrate wasstirred overnight to afford additional batches (2.09 g and 3.1 g)respectively. The solid batches were combined to afford(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(22.3 g, 57%) as a crystalline solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.70(d, J=2.3 Hz, 1H), 8.68 (s, 1H), 8.42 (d, J=2.0 Hz, 1H), 7.93 (s, 1H),7.27 (d, J=2.0 Hz, 1H), 7.23-7.26 (m, 1H), 7.06 (d, J=8.2 Hz, 1H), 4.28(t, J=8.2 Hz, 1H), 4.03 (t, J=6.4 Hz, 2H), 3.86 (t, J=9.0 Hz, 1H), 3.81(s, 3H), 3.46-3.54 (m, 1H), 1.71-1.80 (m, 2H), 1.28-1.35 (m, 1H), 1.15(dd, J=10.5, 16.4 Hz, 1H), 1.00 (t, J=7.4 Hz, 3H). LCMS m/z=328 [MH]⁺,RT [Analytical SFC Method B]=7.30 min. [α]²⁰ _(D) −23.7 (c=0.9, EtOH).Elemental analysis calculated (%) for C₁₈H₂₂BNO₄: C, 66.08, H, 6.78, N,4.28. Found: C, 65.86, H, 6.59, N, 4.18.

Method B:

Step 1: To THF (18.0 mL) was added3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(Preparation 50, 3.0 g, 7.25 mmol), [Ir(COD)Cl]₂ (CAS 12112-67-3, 36.9mg, 0.054 mmol) and(S)[(S_(p))-2-(diphenylphosphino)ferrocenyl]-4-isopropyloxazoline (CAS163169-29-7, 52.4 mg, 0.109 mmol). Additional THF (6.0 mL) was added tothe mixture which was warmed to about 50° C. for about 5 min.Catecholborane (10.9 mL, 1.0M in THF) was added to the mixture andstirred at about 50° C. for about 1 h. The mixture was cooled to about20° C. and treated with HCl (12.2 M, 1.51 mL) over 1 min. The mixturewas held at about 20° C. for about 1 h, after which a precipitate hadformed. The mixture was cooled to about 10° C. and filtered. Thefiltered solid was washed with THF (6.0 mL) and dried overnight at 35°C. under vacuum to afford(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridine-3-yl)-1,2-oxaborolan-2-olhydrochloride monohydrate (3.98 g, 91%) as a crystalline solid. ¹H NMR(CD₃OD, 400 MHz): δ 8.98 (d, J=1.5 Hz, 1H), 8.75 (s, 1H), 8.67 (d, J=1.3Hz, 1H), 7.37-7.43 (m, 2H), 7.15 (d, J=8.3 Hz, 1H), 4.09 (t, J=6.5 Hz,2H), 3.89-3.92 (m, 1H), 3.86-3.95 (m, 5H), 3.46 (br s, 1H), 1.85 (m,2H), 1.31-1.42 (m, 2H), 1.08 (t, J=7.4 Hz, 3H). LCMS m/z=328 [MH]⁺.

Step 2: To a solution of(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridine-3-yl)-1,2-oxaborolan-2-olhydrochloride monohydrate (2.0 g, 5.24 mmol) in water (60 mL) was addedEtOAc (20 mL). To the stirred mixture was added NaOH (1N) dropwise toadjust the pH of the aqeuous layer to 7-8. The mixture was stirred atabout 20° C. for about 5 min. The layers were separated and the aqueouslayer was extracted with EtOAc (2×10 mL). The combined EtOAc extractswere concentrated. The residue was dissolved in THF/MTBE (1:3, 22 mL)and stirred at about 20° C. overnight. The precipitate was filtered anddried under vacuum to afford(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridine-3-yl)-1,2-oxaborolan-2-ol(1.17 g, 68%) as a crystalline solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.70(d, J=2.3 Hz, 1H), 8.68 (s, 1H), 8.42 (d, J=2.0 Hz, 1H), 7.93 (s, 1H),7.27 (d, J=2.0 Hz, 1H), 7.23-7.26 (m, 1H), 7.06 (d, J=8.2 Hz, 1H), 4.28(t, J=8.2 Hz, 1H), 4.03 (t, J=6.4 Hz, 2H), 3.86 (t, J=9.0 Hz, 1H), 3.81(s, 3H), 3.46-3.54 (m, 1H), 1.71-1.80 (m, 2H), 1.28-1.35 (m, 1H), 1.15(dd, J=10.5, 16.4 Hz, 1H), 1.00 (t, J=7.4 Hz, 3H). LCMS m/z=328 [MH]⁺.

Method C:

To a solution of(R)-(3-((tert-butyldimethylsilyl)oxy)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)propyl)boronicacid (Preparation 6, 29.0 g, 63.1 mmol) in THF (66 mL) was added aqueousHCl (84.2 mL, 252 mmol, 3.0 M) and stirred at 20° C. for about 1.5 h.The mixture was concentrated. The mixture was diluted with 1 M HCl andextracted with EtOAc (3×100 mL). The combined EtOAc extracts were washedwith 1 M HCl (3×50 mL). The combined aqueous extracts were neutralizedwith K₃PO₄ to pH 7-8 and extracted with EtOAc (3×100 mL). The combinedEtOAc extracts were dried over Na₂SO₄, filtered and concentrated toafford(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(19.0 g, 92%). This was further purified by preparative SFC (Prep SFCMethod C) to afford 18 g of the crude product. The crude product wasdissolved in MeOH (100 mL) and water (50 mL). The mixture waspartitioned between brine and EtOAc. The layers were separated and theaqueous layer was extracted with EtOAc. The combined EtOAc extracts werewashed with brine, dried over Na₂SO₄ and concentrated to afford 15 g ofproduct. The residue was dissolved in EtOAc (60 mL) and heptane (30 mL)was slowly added over about 3 h. The mixture was stirred at about 20° C.overnight. The precipitate was filtered and dried to afford (8.08 g).This process was repeated 2 more times to afford additional batches(2.01 g and 1.03 g), respectively. The three batches were combined inheptane (100 mL), chilled to about −78° C. for about 10 min, filteredand dried to afford(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(10.4 g, 51%) as a crystalline solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.70(d, J=2.3 Hz, 1H), 8.68 (s, 1H), 8.42 (d, J=2.0 Hz, 1H), 7.93 (s, 1H),7.27 (d, J=2.0 Hz, 1H), 7.23-7.26 (m, 1H), 7.06 (d, J=8.2 Hz, 1H), 4.28(t, J=8.2 Hz, 1H), 4.03 (t, J=6.4 Hz, 2H), 3.86 (t, J=9.0 Hz, 1H), 3.81(s, 3H), 3.46-3.54 (m, 1H), 1.71-1.80 (m, 2H), 1.28-1.35 (m, 1H), 1.15(dd, J=10.5, 16.4 Hz, 1H), 1.00 (t, J=7.4 Hz, 3H). LCMS m/z=328 [MH]⁺.

Example 5:(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

A mixture of3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(Preparation 50, 30 g, 73 mmol), [Ir(COD)Cl]₂ (CAS 12112-67-3, 1.22 g,1.81 mmol),(R,R)-[2-(4′-i-propyloxazolin-2-yl)ferrocenyl]diphenylphosphine (CAS541540-70-9, 1.75 g, 3.63 mmol) and THF (240 mL) was cooled in an icebath for about 30 min. A solution of catecholborane (109 mL, 109 mmol,1.0 M in THF) was added slowly over about 20 min, after which themixture was stirred at about 20° C. for about 3 h. The reaction wasquenched with MeOH (30 mL). The mixture was concentrated and driedovernight. The residue was treated with 3 M aqueous HCl/THF (1:1, v/v)for about 2 h and washed with EtOAc. The aqueous layer was separated andneutralized to pH 7-8 and extracted with EtOAc. The EtOAc extract wasdried over Na₂SO₄, filtered and concentrated. The residue was dissolvedin THF/MTBE (1:1, 180 mL) and stirred with Biotage MP-TMT resin (28 g,Biotage P/N 801470) at about 20° C., under N₂, overnight. The mixturewas filtered and the resin was washed with THF (2×50 mL). The combinedTHF/MTBE filtrates were concentrated to afford(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(23.5 g, 71%). This was further purified via SFC purification (Prep SFCMethod C) to afford 12 g of a crude product. The crude product wasdissolved in MeOH (35 mL) and water (15 mL). The mixture was partitionedbetween brine and EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAC. The combined EtOAc extracts were dried overNa₂SO₄, filtered and concentrated. The residue was dissolved in EtOAc(30 mL) and heptane was added until just cloudy. The mixture was stirredovernight. The precipitate was filtered and dried to afford(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(5.39 g, 45%) as a crystalline solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.70(d, J=2.3 Hz, 1H), 8.68 (s, 1H), 8.42 (d, J=2.0 Hz, 1H), 7.93 (s, 1H),7.27 (d, J=2.0 Hz, 1H), 7.23-7.26 (m, 1H), 7.06 (d, J=8.2 Hz, 1H), 4.28(t, J=8.2 Hz, 1H), 4.03 (t, J=6.4 Hz, 2H), 3.86 (t, J=9.0 Hz, 1H), 3.81(s, 3H), 3.46-3.54 (m, 1H), 1.71-1.80 (m, 2H), 1.28-1.35 (m, 1H), 1.15(dd, J=10.5, 16.4 Hz, 1H), 1.00 (t, J=7.4 Hz, 3H). LCMS m/z=328 [MH]⁺,RT [Analytical SFC Method B]=6.35 min. [α]²⁰ _(D) +27.3 (c=0.6, EtOH).Elemental analysis calculated (%) for C₁₈H₂₂BN₄: C, 66.08, H, 6.78, N,4.28. Found: C, 66.01, H, 6.52, N, 4.15.

Example6:4-(5-(3-isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 1

4-(5-(3-isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 35, 90 mg, 0.28 mmol) was further purified by preparative SFC(Prep SFC Method D) followed by preparative HPLC (Method A) to afford4-(5-(3-isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 1 (17 mg, 19%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (s, 1H),8.69 (d, J=2.0 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 7.92 (t, J=2.0 Hz, 1H),7.29-7.24 (m, 2H), 7.07 (d, J=8.0 Hz, 1H), 4.68-4.74 (m, 1H), 4.27 (t,J=8.3 Hz, 1H), 3.86 (t, J=9.0 Hz, 1H), 3.79 (s, 3H), 3.47-3.55 (m, 1H),1.26-1.35 (m, 7H), 1.10-1.18 (m, 1H). LCMS m/z=328 [MH]⁺. RT [AnalyticalSFC Method C]=5.425 min.

Example7:4-(5-(3-cyclopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 2

4-(5-(3-cyclopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 36, 5.0 g, 4.54 mmol) was further purified by preparative SFC(Prep SFC Method E) to afford4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 2 (205 mg, 41%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.69-8.72 (m,2H), 8.44 (d, J=2.0 Hz, 1H), 7.91 (t, J=2.0 Hz, 1H), 7.53 (d, J=2.0 Hz,1H), 7.28 (dd, J=2.4, 8.3 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 4.25-4.31 (m,1H), 3.97-4.01 (m, 1H), 3.86 (t, J=8.8 Hz, 1H), 3.78 (s, 3H), 3.46-3.57(m, 1H), 1.32 (dd, J=8.1, 16.4 Hz, 1H), 1.14 (dd, J=10.3, 16.1 Hz, 1H),0.76-0.83 (m, 2H), 0.67-0.72 (m, 2H). LCMS m/z=326 [MH]⁺. RT [AnalyticalSFC Method D]=5.736 min.

Example 8: (−)4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 1

4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 37, 1.5 g, 4.56 mmol) was further purified by preparative SFC(Prep SFC Method F) to afford4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 1 (261 mg, 27%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.70-8.72 (m,2H), 8.42 (d, J=2.0 Hz, 1H), 7.94 (t, J=2.2 Hz, 1H), 7.30 (d, J=2.0 Hz,1H), 7.26 (dd, J=2.1, 8.4 Hz, 1H), 7.07 (d, J=8.6 Hz, 1H), 4.88 (t,J=5.4 Hz, 1H), 4.25-4.30 (m, 1H), 4.09 (t, J=5.0 Hz, 2H), 3.86 (t, J=9.0Hz, 1H), 3.81 (s, 3H), 3.75 (q, J=5.2 Hz, 2H), 3.46-3.53 (m, 1H),1.28-1.34 (m, 1H), 1.15 (dd, J=10.5, 16.1 Hz, 1H). LCMS m/z=348[MH+H₂]⁺, RT [Analytical SFC Method D]=3.357 min. [α]²⁰ _(D) −25.9(c=0.1, EtOH).

Example 9: (−)4-(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 2

4-(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 38, 1.2 g, 7.28 mmol) was further purified by preparative SFC(Prep SFC Method G) to afford4-(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 2 (639 mg, 35%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.68-8.72 (m,2H), 8.43 (d, J=2.0 Hz, 1H), 7.94 (t, J=2.0 Hz, 1H), 7.29 (d, J=2.0 Hz,1H), 7.23-7.27 (m, 1H), 7.06 (d, J=8.5 Hz, 1H), 4.55 (t, J=5.1 Hz, 1H),4.27 (t, J=8.3 Hz, 1H), 4.14 (t, J=6.4 Hz, 2H), 3.86 (t, J=9.0 Hz, 1H),3.80 (s, 3H), 3.58 (q, J=6.0 Hz, 2H), 3.44-3.55 (m, 1H), 1.86-1.92 (m,2H), 1.27-1.35 (m, 1H), 1.11-1.19 (m, 1H). LCMS m/z=344 [MH]⁺; RT[Analytical SFC Method F]=1.060 min. [α]²⁰ _(D) −19.5 (c=0.02, EtOH).

Example 10: (−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 1

4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 41, 800 mg, 2.20 mmol) was further purified by preparative SFC(Prep SFC Method H) to afford4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 1 (308 mg, 39%). The material was recrystallized fromEtOAc/heptane (1:1, v/v) to afford a crystalline solid. ¹H NMR (DMSO-d₆,400 MHz): δ 8.69 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.34 (d, J=1.5 Hz,1H), 7.61 (s, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.80-7.14 (m, 2H), 4.27 (t,J=8.3 Hz, 1H), 4.08 (q, J=6.8 Hz, 2H), 3.89 (s, 3H), 3.80 (t, J=8.8 Hz,1H), 3.45-3.54 (m, 1H), 1.25-1.38 (m, 4H), 1.00-1.12 (m, 1H). LCMSm/z=364 [MH]⁺; RT [Analytical SFC Method E]=3.640 min. [α]²³ _(D) −27.5(c=0.2, EtOH).

Example 11: (+)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 2

Further elution of the preparative SFC column (Prep SFC Method H)described in Example 10 provided4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 2 (259 mg, 32%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.69 (s, 1H),8.48 (d, J=2.0 Hz, 1H), 8.34 (d, J=1.5 Hz, 1H), 7.61 (s, 1H), 7.31 (d,J=8.8 Hz, 1H), 6.80-7.14 (m, 2H), 4.27 (t, J=8.3 Hz, 1H), 4.08 (q, J=6.8Hz, 2H), 3.89 (s, 3H), 3.80 (t, J=8.8 Hz, 1H), 3.45-3.54 (m, 1H),1.25-1.38 (m, 4H), 1.00-1.12 (m, 1H). LCMS m/z=364 [MH]⁺; RT [AnalyticalSFC Method E]=4.050 min. [α]²³ _(D) +18.3 (c=0.2, EtOH).

Example 12:4-(5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 1

4-(5-(3-Ethoxy-5-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 44, 60 mg, 0.18 mmol) was further purified by preparative SFC(Prep SFC Method I) to afford4-(5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 1 (18 mg, 30%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.75 (d, J=2.0Hz, 1H), 8.71 (s, 1H), 8.47 (d, J=1.47 Hz, 1H), 8.00 (s, 1H), 7.27 (dd,J=2.0, 11.7 Hz, 1H), 7.20 (s, 1H), 4.27 (t, J=8.3 Hz, 1H), 4.21 (q,J=6.9 Hz, 2H), 3.82-3.90 (m, 3H), 3.45-3.56 (m, 2H), 1.39 (t, J=6.9 Hz,3H), 1.26-1.34 (m, 1H), 1.12-1.20 (m, 1H). LCMS m/z=350 [MH+H₂O]⁺; RT[Analytical SFC Method D]=4.282 min.

Example 13:4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olenantiomer 1

4-(5-(3-Chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 45, 150 mg, 0.43 mmol) was further purified by preparative SFC(Prep SFC Method J) to afford4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 1 (411.3 mg, 37%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.75 (d,J=2.0 Hz, 1H), 8.70 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.02 (t, J=2.2 Hz,1H), 7.42 (d, J=2.0 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 4.18-4.30 (m, 3H),3.83-3.91 (m, 1H), 3.81 (s, 3H), 3.44-3.57 (m, 1H), 1.39 (t, J=6.9 Hz,3H), 1.26-1.34 (m, 1H), 1.12-1.22 (m, 1H). LCMS m/z=348 [MH]⁺; RT[Analytical SFC Method D]=4.932 min.

Example 14:4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 2

4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 46, 385 mg, 1.16 mmol) was further purified by preparative SFC(Prep SFC Method K) to afford4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 2 (122 mg, 32%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (s, 1H),8.58 (s, 1H), 8.46 (s, 1H), 7.83 (s, 1H), 7.09 (d, J=7.7 Hz, 1H), 7.03(d, J=12.4 Hz, 1H), 4.28 (t, J=8.2 Hz, 1H), 4.07 (q, J=7.0 Hz, 2H),3.82-3.86 (m, 4H), 3.46-3.55 (m, 1H), 1.29-1.34 (m, 4H), 1.07-1.14 (m,1H). LCMS m/z=332 [MH]⁺; RT [Analytical SFC Method D]=4.111 min.

Example 15: (−)4-(5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 2

4-(5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 47, 1.6 g, 4.60 mmol) was further purified by preparative SFC(Prep SFC Method L) to afford4-(5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 2 (550 mg, 34%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H),8.48 (t, J=2.0 Hz, 2H), 7.76 (t, J=2.2 Hz, 1H), 7.15 (s, 1H), 7.01 (s,1H), 4.26-4.30 (m, 1H), 4.06 (q, J=7.0 Hz, 2H), 3.81-3.85 (m, 4H),3.47-3.55 (m, 1H), 1.29-1.35 (m, 4H), 1.06-1.12 (m, 1H). LCMS m/z=348[MH]⁺; RT [Analytical SFC Method G]=4.089 min. [α]²⁰ _(D) −18.0 (c=0.1,EtOH).

Example 16: (−)4-(3-fluoro-5-methoxy-6-propoxy-[2,3′-bipyridin]-5′-yl)-1,2-oxaborolan-2-ol,enantiomer 1

4-(3-fluoro-5-methoxy-6-propoxy-[2,3′-bipyridin]-5′-yl)-1,2-oxaborolan-2-ol(Example 48, 770 mg, 2.22 mmol) was further purified by preparative SFC(Prep SFC Method M) to afford4-(3-fluoro-5-methoxy-6-propoxy-[2,3′-bipyridin]-5′-yl)-1,2-oxaborolan-2-ol,enantiomer 1 (298 mg, 39%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.89 (s, 1H),8.73 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.09 (s, 1H), 7.49 (d, J=12.0 Hz,1H), 4.28-4.33 (m, 3H), 3.87 (s, 3H), 3.82 (t, J=8.7 Hz, 1H), 3.49-3.57(m, 1H), 1.73-1.81 (m, 2H), 1.31-1.37 (m, 1H), 1.03-1.09 (m, 1H), 0.98(t, J=7.5 Hz, 3H). LCMS m/z=347 [MH]⁺; RT [Analytical SFC MethodD]=4.347 min. [α]²⁰ _(D) −12.1 (c=0.1, EtOH).

Example 17: (−)4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 1

4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example50, 506 mg, 1.39 mmol) was further purified by preparative SFC (Prep SFCMethod N) to afford4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 1 (165 mg, 33%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.74 (d, J=2.1Hz, 1H), 8.72 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.00 (t, J=2.0 Hz, 1H),7.45 (d, J=1.6 Hz, 1H), 7.28-7.31 (m, 2H), 7.09 (t, J=74.5 Hz, 1H), 4.28(t, J=8.3 Hz, 1H), 4.12 (t, J=6.4 Hz, 2H), 3.87 (t, J=9.1 Hz, 1H),3.47-3.56 (m, 1H), 1.73-1.82 (m, 2H), 1.29-1.35 (m, 1H), 1.12-1.19 (m,1H), 1.01 (t, J=7.5 Hz, 3H). LCMS m/z=381 [MH+H₂O]⁺; RT [Analytical SFCMethod E]=3.402 min. [α]²⁰ _(D) −21.2 (c=0.1, EtOH).

Example 18: (−)4-(6′-methoxy-5′-propoxy-[3,3′-bipyridin]-5-yl)-1,2-oxaborolan-2-ol,enantiomer 1

4-(6′-Methoxy-5′-propoxy-[3,3′-bipyridin]-5-yl)-1,2-oxaborolan-2-ol(Example 51, 1.1 g, 3.4 mmol) was further purified by preparative SFC(Prep SFC Method O) to afford4-(6′-methoxy-5′-propoxy-[3,3′-bipyridin]-5-yl)-1,2-oxaborolan-2-ol,enantiomer 1 (411 mg, 37%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.76 (d, J=2.2Hz, 1H), 8.72 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H),8.01 (t, J=2.2 Hz, 1H), 7.61 (d, J=2.2 Hz, 1H), 4.26-4.31 (m, 1H), 4.08(t, J=6.6 Hz, 2H), 3.92 (s, 3H), 3.87 (t, J=9.1 Hz, 1H), 3.48-3.56 (m,1H), 1.73-1.82 (m, 2H), 1.28-1.35 (m, 1H), 1.13-1.21 (m, 1H), 1.00 (t,J=7.5 Hz, 3H). LCMS m/z=347 [MH+H₂O]⁺; RT [Analytical SFC MethodG]=4.231 min. [α]²⁰ _(D) −27.2 (c=0.1, EtOH).

Example 19:(R)-4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 1

4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol(Example 52, 171.7 mg, 0.53 mmol) was further purified by preparativeSFC (Prep SFC Method P) to afford4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 1, (66 mg, 36%). The material was recrystallized fromEtOAc/heptane to afford a crystalline solid. ¹H NMR (DMSO-d₆, 400 MHz):δ 8.67 (s, 1H), 8.33 (d, J=2.0 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.03 (d,J=8.3 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 6.88 (dd, J=2.0, 7.8 Hz, 1H),4.24 (t, J=8.1 Hz, 1H), 4.04 (q, J=6.9 Hz, 2H), 3.76-3.83 (m, 4H),3.39-3.50 (m, 1H), 2.40 (s, 3H), 1.24-1.36 (m, 4H), 1.01-1.10 (m, 1H).LCMS m/z=328 [MH]⁺; RT [Analytical SFC Method H]=1.768 min. [α]²⁰ _(D)−20.0 (c=0.4, EtOH).

Example 20:(S)-4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 2

Further elution of the preparative SFC column (Prep SFC Method P)described in Example 19 provided4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 2, (69 mg, 40%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.67 (s, 1H),8.33 (d, J=2.0 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H),6.94 (d, J=2.0 Hz, 1H), 6.88 (dd, J=2.0, 7.8 Hz, 1H), 4.24 (t, J=8.1 Hz,1H), 4.04 (q, J=6.9 Hz, 2H), 3.76-3.83 (m, 4H), 3.39-3.50 (m, 1H), 2.40(s, 3H), 1.24-1.36 (m, 4H), 1.01-1.10 (m, 1H). LCMS m/z=328 [MH]⁺; RT[Analytical SFC Method H]=2.168 min.

Example 21:4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 1

4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol(Example 53, 45 mg, 0.14 mmol) was further purified by preparative SFC(Prep SFC Method I) to afford4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol,enantiomer 1 (12.5 mg, 28%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H),8.43 (s, 1H), 8.21 (s, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.90 (d, J=2.3 Hz,1H), 6.82-6.85 (m, 1H), 4.24-4.28 (m, 1H), 4.03 (q, J=7.0 Hz, 2H),3.90-3.95 (m, 1H), 3.80 (s, 3H), 3.63-3.71 (m, 1H), 2.22 (s, 3H),1.30-1.36 (m, 4H), 1.04-1.10 (m, 1H). LCMS m/z=328 [MH]⁺; RT [AnalyticalSFC Method 1]=5.208 min.

Example 22: (−)4-(2-(4-methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol,enantiomer 2

4-(2-(4-methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol(Example54, 2.5 g, 7.28 mmol) was further purified by preparative SFC (Prep SFCMethod Q) to afford4-(2-(4-methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol,enantiomer 2 (68 mg, 22%). ¹H NMR (CD₃OD, 400 MHz): δ 8.03 (dd, J=2.0,8.6 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.07 (s, 1H), 7.05 (d, J=8.3 Hz,1H), 4.17 (br s, 1H), 4.07 (t, J=6.5 Hz, 2H), 4.00 (br s, 1H), 3.91 (s,2H), 3.41 (br s, 1H), 2.52 (s, 2H), 1.84-1.89 (m, 2H), 1.29-1.38 (m,1H), 1.21-1.29 (m, 1H), 1.09 (t, J=7.3 Hz, 3H). LCMS m/z=343 [MH]⁺; RT[Analytical SFC Method J]=3.148 min. [α]²⁰ _(D) −23.2 (c=0.1, EtOH).

Example 23: (−)4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol,enantiomer 2

4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol(Example 55, 572 mg, 1.45 mmol) was further purified by preparative SFC(Prep SFC Method M) to afford4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol,enantiomer 2 (100 mg, 18%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (s, 1H),8.03 (dd, J=2.0, 8.6 Hz, 1H), 7.95 (d, J=2.0 Hz, 1H), 7.77 (s, 1H), 7.13(d, J=8.6 Hz, 1H), 4.32 (dd, J=7.4, 9.0 Hz, 1H), 3.98-4.09 (m, 3H), 3.86(s, 3H), 3.73-3.82 (m, 1H), 1.73-1.84 (m, 1H), 1.31-1.41 (m, 1H),1.18-1.26 (m, 2H), 1.01 (t, J=7.4 Hz, 3H). LCMS m/z=397 [MH]⁺; RT[Analytical SFC Method E]=4.765 min. [α]²⁰ _(D) −12.6 (c=0.4, EtOH).

Example 24:4-(6-(3-ethoxy-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol,enantiomer 2

4-(6-(3-Ethoxy-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol(Example 56, 20 mg, 0.06 mmol) was further purified by preparative SFC(Prep SFC Method R) to afford4-(6-(3-ethoxy-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol,enantiomer 2 (6.4 mg, 34%). LCMS m/z=315 [MH]⁺. RT [Analytical SFCMethod K]=3.23 min.

Example 25:4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborol-2(5H)-ol

A mixture of3-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(Preparation 8, 1.30 g, 2.41 mmol) in AcOH (10 mL) and water (5 mL) wasstirred at about 50° C. for about 1 h. The mixture was concentrated andEtOH (10 mL) was added. The mixture was stirred at about 0° C. for about15 min and filtered. The solid was washed with water (15 mL) and driedto afford4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborol-2(5H)-ol (560mg, 68%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.86 (d, J=2.0 Hz, 1H), 8.77 (s,1H), 8.73 (d, J=2.0 Hz, 1H), 8.14 (t, J=2.0 Hz, 1H), 7.31-7.34 (m, 2H),7.08 (d, J=8.0 Hz, 1H), 6.46 (s, 1H), 5.02 (s, 2H), 4.05 (t, J=6.4 Hz,2H), 3.82 (s, 3H), 1.72-1.81 (m, 2H), 1.01 (t, J=7.6 Hz, 3H). LCMSm/z=326 [MH]⁺.

Example 26:4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborinan-2-ol

2-(4-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-6-(4-methoxy-3-propoxyphenyl)pyridine(Preparation 31, 140 mg, 0.25 mmol) was dissolved in AcOH (4.3 mL) andwater (0.2 mL) and stirred at about 20° C. for about 16 h. The mixturewas concentrated and the residue was purified by preparative HPLC (PrepHPLC Method B) to afford4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-1,2-oxaborinan-2-ol (60mg, 70%). ¹H NMR (DMSO-d₆, 400 MHz): δ 7.71-7.76 (m, 4H), 7.64-7.66 (m,1H), 7.15-7.17 (m, 1H), 7.03 (d, J=8.6 Hz, 1H), 4.02 (t, J=6.6 Hz, 2H),3.64-3.98 (m, 2H), 3.81 (m, 3H), 3.13-3.20 (m, 1H), 1.92-2.00 (m, 1H),1.72-1.82 (m, 3H), 1.09 (d, J=7.0 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). LCMSm/z=342 [MH]⁺.

Example27:4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborolan-2-ol

A mixture of4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborol-2(5H)-ol(Example 28, 50 mg, 0.15 mmol) and Adam's catalyst (10.0 mg, 0.044 mmol)in EtOAc (1.5 mL) was hydrogenated at 20 psig at about 40° C. for about2 h. The reaction was filtered through a Celite® pad and the filtratewas concentrated. The residue was purified by column chromatography(silica) and eluted with heptane/EtOAc (80:20 to 0:100) followed byDCM/MeOH (90:10) to afford4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborolan-2-ol(40 mg, 80%). ¹H NMR (CDCl₃, 400 MHz): δ 7.73 (br s, 1H), 7.51-7.66 (m,4H), 6.92-7.00 (m, 2H), 4.36 (d, J=3.1 Hz, 2H), 4.12 (t, J=6.8 Hz, 2H),3.92 (s, 3H), 3.56 (br s, 1H), 1.87-1.96 (m, 2H), 1.70-1.80 (m, 1H),1.08 (t, J=7.4 Hz, 3H), 0.80 (d, J=7.0 Hz, 3H). LCMS m/z=342 [MH]⁺.

Example 28:4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborol-2(5H)-ol

4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-3-methyl-1,2-oxaborol-2(5H)-ol(105 mg, 46%) was prepared in an analogous manner to Example 25 using3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-2-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(Preparation 32, 370 mg, 0.668 mmol). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.71(s, 1H), 7.86-7.91 (m, 2H), 7.75 (d, J=2.0 Hz, 1H), 7.67 (dd, J=2.0, 8.6Hz, 1H), 7.36-7.44 (m, 1H), 7.07 (d, J=8.6 Hz, 1H), 4.95 (d, J=2.0 Hz,2H), 4.02 (t, J=6.6 Hz, 2H), 3.82 (s, 3H), 2.15 (s, 3H), 1.71-1.85 (m,2H), 1.01 (t, J=7.4 Hz, 3H). LCMS m/z=340 [MH]⁺.

Example 29:4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-4-methyl-1,2-oxaborolan-2-ol

To a solution of ethyl2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propanoate(Preparation 33, 134 mg, 0.277 mmol) in THF (3.0 mL) at about 20° C. wasadded LiBH₄ (6.0 mg, 0.28 mmol), followed by water (0.10 mL). Thereaction mixture was stirred at about 20° C. for about 3 h. Anotherportion of LiBH₄ (25 mg, 1.15 mmol) and water (0.2 mL) was added. Themixture was stirred at about 20° C. for about 5 min. Another portion ofLiBH₄ (25 mg, 1.15 mmol) and water (0.3 mL) was added and stirred atabout 20° C. for about 10 min. The mixture was diluted with water andextracted with EtOAc. The EtOAc extract was washed with brine and driedover Na₂SO₄. The mixture was filtered, concentrated and dissolved in THF(3 mL) and water (1 mL). The solution was treated with excess LiBH₄ atabout 20° C. for about 3 h. The mixture was diluted with water andextracted with EtOAc. The EtOAc extract was washed with brine, driedover Na₂SO₄, filtered and concentrated. The residue was purified bypreparative HPLC (Prep HPLC Method C) to afford4-(6-(4-methoxy-3-propoxyphenyl)pyridin-2-yl)-4-methyl-1,2-oxaborolan-2-ol(46.1 mg, 49%). ¹H NMR (CD₃OD, 500 MHz): δ 7.80 (br s, 1H), 7.74 (d,J=1.5 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.62 (m, 1H), 7.32 (d, J=7.1 Hz,1H), 7.07 (d, J=8.3 Hz, 1H), 5.51 (s, 1H), 4.29 (d, J=8.8 Hz, 1H),4.07-4.16 (m, 3H), 3.92 (s, 3H), 3.47 (m, 1H), 3.19 (m, 1H), 1.88 (m,2H), 1.55 (d, J=16.1 Hz, 1H), 1.51 (s, 3H), 1.20 (d, J=15.7 Hz, 1H),1.10 (t, J=7.3 Hz, 3H). LCMS m/z=342 [MH]⁺.

Example 30:4-(6-(4-methoxy-3-propoxyphenyl)pyridazin-4-yl)-5-methyl-1,2-oxaborolan-2-ol

A mixture of5-(3-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-3-(4-methoxy-3-propoxyphenyl)pyridazine(Preparation 34, 160 mg, 0.29 mmol) in AcOH (6 mL) and water (1 mL) wasstirred at about 70° C. for about 21 h. The mixture was concentrated,dissolved in MeCN (15 mL) and concentrated again. The mixture waspurified by preparative HPLC (Prep HPLC Method D) to afford4-(6-(4-methoxy-3-propoxyphenyl)pyridazin-4-yl)-5-methyl-1,2-oxaborolan-2-ol(10.6 mg, 11%). ¹H NMR (DMSO-d₆, 400 MHz): δ 9.12 (s, 1H), 9.05 (d,J=2.0 Hz, 1H), 8.77 (s, 1H), 8.69 (s, 1H), 8.13 (s, 1H), 7.98 (s, 1H),7.68-7.81 (m, 3H), 7.07-7.16 (m, 2H), 4.64 (t, J=6.5 Hz, 1H), 4.25-4.35(m, 1H), 4.04 (t, J=6.5 Hz, 3H), 3.84 (s, 5H), 3.64 (d, J=9.0 Hz, 1H),2.92-3.01 (m, 1H), 1.74-1.83 (m, 3H), 1.48 (dd, J=10.0, 16.1 Hz, 1H),1.24-1.39 (m, 2H), 1.17 (d, J=6.0 Hz, 3H), 1.01 (t, J=7.0 Hz, 6H), 0.77(d, J=7.0 Hz, 1H). LCMS m/z=343 [MH]⁺.

Example 31:4-(hydroxymethyl)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

Turbo Grignard (0.5 mL, 1.3 M in THF) was stirred with anhydrous1,4-dioxane (0.05 mL) at about 20° C. under N₂ for about 30 min toafford a mixture which was used directly in the following procedure(Reagent A). To a solution of3-(5-(iodomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(Preparation 77, 120 mg, 0.25 mmol) in THF (0.50 mL) under N₂ was addedReagent A. The mixture was stirred at about 20° C. for about 1 h.Trimethyl borate (0.33 mL, 2.98 mmol) was added and stirred at about 20°C. under N₂ for about 1 h. The cooled mixture was treated with HCl inIPA (5.5 M, 0.45 mL, 2.48 mmol) for about 1 h. The mixture was dilutedwith 1 M HCl and washed with EtOAc. The EtOAc layer was extracted with 1M HCl (2×5 mL). The combined aqueous extracts were neutralized to pH 6-7with K₃PO₄. The aqueous extract was extracted with EtOAc (3×10 mL). Thecombined EtOAc extracts were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by preparative SFC (Prep SFCMethod S) to afford4-(hydroxymethyl)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(38 mg, 43%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.69 (d, J=2.0 Hz, 1H), 8.63(s, 1H), 8.37 (d, J=2.0 Hz, 1H), 7.75 (m, 1H), 7.19-7.28 (m, 2H), 7.08(d, J=8.6 Hz, 1H), 4.99 (m, 1H), 4.39 (d, J=9.0 Hz, 1H), 4.00-4.13 (m,4H), 3.82 (s, 3H), 3.47 (br s, 2H), 1.77 (m, 2H), 1.28-1.38 (m, 1H),1.14-1.22 (m, 1H), 0.96-1.08 (m, 3H). LCMS m/z=358 [MH]⁺.

Example 32: 4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

A mixture of3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3,4-dimethoxyphenyl)pyridine(Preparation 1, 1.0 g, 1.95 mmol) in AcOH (15 mL), THF (5 mL) and water(5 mL) was stirred at about 55° C. for about 6 h. The mixture wasconcentrated and the residue was purified by preparative HPLC (Prep HPLCMethod E) to afford4-(5-(3,4-dimethoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol (98 mg,17%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (d, J=2.8 Hz, 2H), 8.43 (d,J=2.0 Hz, 1H), 7.95 (t, J=2.0 Hz, 1H), 7.25-7.29 (m, 1H), 7.06 (d, J=8.4Hz, 2H), 4.28 (t, J=4.28 Hz, 1H), 3.84-3.88 (m, 4H), 3.80 (s, 3H),3.46-3.54 (m, 1H), 1.28-1.34 (m, 1H), 1.12-1.18 (m, 1H). LCMS m/z=300[MH]⁺.

Example 33:4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

A mixture of3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)pyridine(Preparation 3, 3.80 g, 7.20 mmol) in AcOH (60 mL) and water (10 mL) wasstirred at about 50° C. for about 1 h. The mixture was concentrated andthe residue was purified by preparative HPLC (Prep HPLC Method F) toafford 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(810 mg, 34%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.70 (d, J=2.3 Hz, 1H), 8.68(s, 1H), 8.42 (d, J=1.6 Hz, 1H), 7.92-7.94 (m, 1H), 7.23-7.29 (m, 2H),7.06 (d, J=8.2 Hz, 1H), 4.28 (t, J=8.2 Hz, 1H), 4.13 (q, J=6.8 Hz, 2H),3.86 (t, J=9.0 Hz, 1H), 3.80 (s, 3H), 3.45-3.55 (m, 1H), 1.28-1.39 (m,4H), 1.10-1.20 (m, 1H). LCMS m/z=314 [MH]⁺.

Example 34:4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

A mixture of3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine(Preparation 5, 3.44 g, 6.35 mmol) in AcOH (60 mL) and water (10 mL) wasstirred at about 50° C. for about 1 h. The mixture was concentrated andthe residue was purified by preparative HPLC (Prep HPLC Method G) toafford 4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(1.04 g, 49%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.70 (d, J=2.3 Hz, 1H), 8.68(s, 1H), 8.42 (d, J=2.0 Hz, 1H), 7.93 (s, 1H), 7.27 (d, J=2.0 Hz, 1H),7.23-7.26 (m, 1H), 7.06 (d, J=8.2 Hz, 1H), 4.28 (t, J=8.2 Hz, 1H), 4.03(t, J=6.4 Hz, 2H), 3.86 (t, J=9.0 Hz, 1H), 3.81 (s, 3H), 3.46-3.54 (m,1H), 1.71-1.80 (m, 2H), 1.28-1.35 (m, 1H), 1.15 (dd, J=10.5, 16.4 Hz,1H), 1.00 (t, J=7.4 Hz, 3H). LCMS m/z=328 [MH]⁺.

Example 35:4-(5-(3-isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-isopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(103 mg, 43%) was prepared in an analogous manner to Example 33 using3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-isopropoxy-4-methoxyphenyl)pyridine(Preparation 9, 400 mg, 0.74 mmol) and purified by preparative HPLC(Prep HPLC Method H). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (s, 1H), 8.69(d, J=2.0 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 7.92 (t, J=2.0 Hz, 1H),7.29-7.24 (m, 2H), 7.07 (d, J=8.0 Hz, 1H), 4.68-4.74 (m, 1H), 4.27 (t,J=8.3 Hz, 1H), 3.86 (t, J=9.0 Hz, 1H), 3.79 (s, 3H), 3.47-3.55 (m, 1H),1.26-1.35 (m, 7H), 1.10-1.18 (m, 1H). LCMS m/z=328 [MH]⁺.

Example 36:4-(5-(3-cyclopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-cyclopropoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(45 mg, 10%) was prepared in an analogous manner to Example 33 using3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-cyclopropoxy-4-methoxyphenyl)pyridine(Preparation 10, 750 mg, 1.39 mmol) and purified by preparative HPLC(Prep HPLC Method I). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.69-8.72 (m, 2H),8.44 (d, J=2.0 Hz, 1H), 7.91 (t, J=2.0 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H),7.28 (dd, J=2.4, 8.3 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 4.25-4.31 (m, 1H),3.97-4.01 (m, 1H), 3.86 (t, J=8.8 Hz, 1H), 3.78 (s, 3H), 3.46-3.57 (m,1H), 1.32 (dd, J=8.1, 16.4 Hz, 1H), 1.14 (dd, J=10.3, 16.1 Hz, 1H),0.76-0.83 (m, 2H), 0.67-0.72 (m, 2H). LCMS m/z=326 [MH]⁺.

Example 37:4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-(2-hydroxyethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(1.5 g, 75%) was prepared in an analogous manner to Example 33 using3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methoxyphenyl)pyridine(Preparation 11, 4.0 g, 6.1 mmol) and purified by preparative HPLC (PrepHPLC Method J). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.70-8.72 (m, 2H), 8.42 (d,J=2.0 Hz, 1H), 7.94 (t, J=2.2 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.26 (dd,J=2.1, 8.4 Hz, 1H), 7.07 (d, J=8.6 Hz, 1H), 4.88 (t, J=5.4 Hz, 1H),4.25-4.30 (m, 1H), 4.09 (t, J=5.0 Hz, 2H), 3.86 (t, J=9.0 Hz, 1H), 3.81(s, 3H), 3.75 (q, J=5.2 Hz, 2H), 3.46-3.53 (m, 1H), 1.28-1.34 (m, 1H),1.15 (dd, J=10.5, 16.1 Hz, 1H). LCMS m/z=330 [MH]⁺.

Example 38:4-(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-(3-hydroxypropoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(2.5 g, 41%) was prepared in an analogous manner to Example 33 using3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-methoxyphenyl)pyridine(Preparation 12, 12 g, 18.0 mmol) and purified by preparative HPLC (PrepHPLC Method K). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.68-8.72 (m, 2H), 8.43 (d,J=2.0 Hz, 1H), 7.94 (t, J=2.0 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.23-7.27(m, 1H), 7.06 (d, J=8.5 Hz, 1H), 4.55 (t, J=5.1 Hz, 1H), 4.27 (t, J=8.3Hz, 1H), 4.14 (t, J=6.4 Hz, 2H), 3.86 (t, J=9.0 Hz, 1H), 3.80 (s, 3H),3.58 (q, J=6.0 Hz, 2H), 3.44-3.55 (m, 1H), 1.86-1.92 (m, 2H), 1.27-1.35(m, 1H), 1.11-1.19 (m, 1H). LCMS m/z=344 [MH]⁺.

Example 39:4-(5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(122 mg, 29%) was prepared in an analogous manner to Example 33 using3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-(2-fluoroethoxy)-4-methoxyphenyl)pyridine(Preparation 13, 700 mg, 1.28 mmol) and purified by preparative HPLC(Prep HPLC Method L). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.71-8.78 (m, 2H),8.44 (d, J=1.5 Hz, 1H), 7.96 (t, J=2.0 Hz, 1H), 7.30-7.37 (m, 2H), 7.10(d, J=8.0 Hz, 1H), 4.81-4.87 (m, 1H), 4.70-4.75 (m, 1H), 4.38-4.43 (m,1H), 4.30-4.34 (m, 1H), 4.27 (d, J=8.5 Hz, 1H), 3.87 (t, J=9.0 Hz, 1H),3.83 (s, 3H), 3.47-3.57 (m, 1H), 1.32 (dd, J=8.3, 16.3 Hz, 1H),1.10-1.21 (m, 1H). LCMS m/z=332 [MH]⁺.

Example 40:4-(3′-(3-fluoropropoxy)-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-ol

4-(3′-(3-fluoropropoxy)-4′-methoxy-[1,1′-biphenyl]-3-yl)-1,2-oxaborolan-2-olwas prepared in an analogous manner Example 33 usingtert-butyl(2-(3′-(3-fluoropropoxy)-4′-methoxy-[1,1′-biphenyl]-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propoxy)dimethylsilane(Preparation 14). ¹H NMR (DMSO-d₆, 400 MHz): δ 7.50 (br s, 1H), 7.46 (d,J=7.8 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H) 7.18-7.25 (m, 3H), 7.04 (d, J=8.2Hz, 1H), 4.69 (t, J=5.9 Hz, 1H), 4.57 (t, J=5.9 Hz, 1H), 4.26 (t, J=7.8Hz, 1H), 4.02-4.18 (m, 3H), 3.80 (s, 3H), 3.42-3.51 (m, 1H), 2.07-2.19(m, 2H), 1.22-1.32 (m, 1H), 1.05-1.12 (m, 1H). LCMS m/z=345 [MH]⁺.

Example 41:4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-olwas prepared (80 mg, 42%) in an analogous manner to Example 33 using3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridine(Preparation 15, 300 mg, 0.519 mmol) and purified by preparative HPLC(Prep HPLC Method M). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.69 (s, 1H), 8.48(d, J=2.0 Hz, 1H), 8.34 (d, J=1.5 Hz, 1H), 7.61 (s, 1H), 7.31 (d, J=8.8Hz, 1H), 6.80-7.14 (m, 2H), 4.27 (t, J=8.3 Hz, 1H), 4.08 (q, J=6.8 Hz,2H), 3.89 (s, 3H), 3.80 (t, J=8.8 Hz, 1H), 3.45-3.54 (m, 1H), 1.25-1.38(m, 4H), 1.00-1.12 (m, 1H). LCMS m/z=364 [MH]⁺.

Example 42:3′-(2-hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-3-propoxy-[1,1′-biphenyl]-2-carbonitrile

To a solution of3′-(2-hydroxy-2,5-dihydro-1,2-oxaborol-4-yl)-4-methoxy-3-propoxy-[1,1′-biphenyl]-2-carbonitrile(Example 43, 500 mg, 1.43 mmol) in EtOAc (15 mL) was added PtO₂ (16 mg,72 umol) under N₂. The mixture was stirred under H₂ (15 psi) at about 0°C. for about 2 h. The mixture was filtered and concentrated. The residuewas purified by preparative HPLC (Prep HPLC Method N) to afford3′-(2-hydroxy-1,2-oxaborolan-4-yl)-4-methoxy-3-propoxy-[1,1′-biphenyl]-2-carbonitrile(284 mg, 55%). ¹H NMR (DMSO-d₆, 400 MHz): δ 7.45 (d, J=8.8 Hz, 2H), 7.41(d, J=7.2 Hz, 1H), 7.34 (t, J=7.2 Hz, 2H), 7.26 (d, J=8.8 Hz, 1H), 4.26(t, J=8.0 Hz, 1H), 4.12 (t, J=6.0 Hz, 2H), 3.89 (s, 3H), 3.81 (t, J=8.8Hz, 1H), 3.43-3.52 (m, 1H), 1.69-1.78 (m, 2H), 1.29 (q, J=8.0 Hz, 1H).1.07-1.11 (m, 1H), 1.01 (t, J=7.6 Hz, 3H). LCMS m/z=352 [MH]⁺.

Example 43:3′-(2-hydroxy-2,5-dihydro-1,2-oxaborol-4-yl)-4-methoxy-3-propoxy-[1,1′-biphenyl]-2-carbonitrile

To a mixture of methyl2-(2′-cyano-4′-methoxy-3′-propoxy-[1,1′-biphenyl]-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate(Preparation 30, 13.6 g, 28.5 mmol) in THF (150 mL) and MeOH (5 mL) wasadded NaBH₄ (754 mg, 19.9 mmol) slowly at about 0° C. The mixture wasstirred at about 20° C. for about 1 h. Water (150 mL) was added and themixture was extracted with EtOAc (2×150 mL). The combined EtOAc extractswere washed with brine (150 mL), dried with Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (silica)and eluted with pet. ether/EtOAc (10:1), then re-crystallized from EtOH(30 mL) at about 0° C. to afford3′-(2-hydroxy-2,5-dihydro-1,2-oxaborol-4-yl)-4-methoxy-3-propoxy-[1,1′-biphenyl]-2-carbonitrile(2.60 g, 26%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H), 7.70 (s, 1H),7.64-7.65 (m, 1H), 7.53 (d, J=4.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 1H), 7.33(d, J=8.4 Hz, 1H), 6.27 (s, 1H), 4.95 (s, 2H), 4.13 (t, J=6.4 Hz, 2H),3.91 (s, 3H), 1.69-1.77 (m, 2H), 1.02 (t, J=7.2 Hz, 3H). LCMS m/z=350[MH]⁺.

Example 44:4-(5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(90 mg, 25%) was prepared in an analogous manner to Example 33 using3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-ethoxy-5-fluoro-4-methoxyphenyl)pyridine(Preparation 16, 600 mg, 1.1 mmol) and purified by preparative HPLC(Prep HPLC Method 0). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.75 (d, J=2.0 Hz,1H), 8.71 (s, 1H), 8.47 (d, J=1.47 Hz, 1H), 8.00 (s, 1H), 7.27 (dd,J=2.0, 11.7 Hz, 1H), 7.20 (s, 1H), 4.27 (t, J=8.3 Hz, 1H), 4.21 (q,J=6.9 Hz, 2H), 3.82-3.90 (m, 3H), 3.45-3.56 (m, 2H), 1.39 (t, J=6.9 Hz,3H), 1.26-1.34 (m, 1H), 1.12-1.20 (m, 1H). LCMS m/z=332 [MH]⁺.

Example 45:4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(150 mg, 30%) was prepared in an analogous manner to Example 33 using3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-chloro-5-ethoxy-4-methoxyphenyl)pyridine(Preparation 17, 800 mg, 1.42 mmol) and purified by preparative HPLC(Prep HPLC Method P). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.75 (d, J=2.0 Hz,1H), 8.70 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.02 (t, J=2.2 Hz, 1H), 7.42(d, J=2.0 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 4.18-4.30 (m, 3H), 3.83-3.91(m, 1H), 3.81 (s, 3H), 3.44-3.57 (m, 1H), 1.39 (t, J=6.9 Hz, 3H),1.26-1.34 (m, 1H), 1.12-1.22 (m, 1H). LCMS m/z=347 [MH]⁺.

Example 46:4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(385 mg, 32%) was prepared in an analogous manner to Example 33 using3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(5-ethoxy-2-fluoro-4-methoxyphenyl)pyridine(Preparation 18, 2.0 g, 3.67 mmol) and purified by preparative HPLC(Prep HPLC Method Q). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (s, 1H), 8.58(s, 1H), 8.46 (s, 1H), 7.83 (s, 1H), 7.09 (d, J=7.7 Hz, 1H), 7.03 (d,J=12.4 Hz, 1H), 4.28 (t, J=8.2 Hz, 1H), 4.07 (q, J=7.0 Hz, 2H),3.82-3.86 (m, 4H), 3.46-3.55 (m, 1H), 1.29-1.34 (m, 4H), 1.07-1.14 (m,1H). LCMS m/z=332 [MH]⁺.

Example 47:4-(5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(1.6g, 65%) was prepared in an analogous manner to Example 33 using3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(2-chloro-5-ethoxy-4-methoxyphenyl)pyridine(Preparation 19, 4.1 g, 7.30 mmol) and purified by preparative HPLC(Prep HPLC Method R). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H), 8.48(t, J=2.0 Hz, 2H), 7.76 (t, J=2.2 Hz, 1H), 7.15 (s, 1H), 7.01 (s, 1H),4.26-4.30 (m, 1H), 4.06 (q, J=7.0 Hz, 2H), 3.81-3.85 (m, 4H), 3.47-3.55(m, 1H), 1.29-1.35 (m, 4H), 1.06-1.12 (m, 1H). LCMS m/z=348 [MH]⁺.

Example 48:4-(3-fluoro-5-methoxy-6-propoxy-[2,3′-bipyridin]-5′-yl)-1,2-oxaborolan-2-ol

4-(3-fluoro-5-methoxy-6-propoxy-[2,3′-bipyridin]-5′-yl)-1,2-oxaborolan-2-ol(780 mg, 49%) was prepared in an analogous manner to Example 33 using5′-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-3-fluoro-5-methoxy-6-propoxy-2,3′-bipyridine(Preparation 22, 4.02 g, 7.14 mmol) and purified by preparative HPLC(Prep HPLC Method S). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.89 (s, 1H), 8.73(s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.09 (s, 1H), 7.49 (d, J=12.0 Hz, 1H),4.28-4.33 (m, 3H), 3.87 (s, 3H), 3.82 (t, J=8.7 Hz, 1H), 3.49-3.57 (m,1H), 1.73-1.81 (m, 2H), 1.31-1.37 (m, 1H), 1.03-1.09 (m, 1H), 0.98 (t,J=7.5 Hz, 3H). LCMS m/z=347 [MH]⁺.

Example 49:4-(5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(1.2g, 49%) was prepared in an analogous manner to Example 33 using3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(2-fluoro-4-methoxy-5-propoxyphenyl)pyridine(Preparation 20, 4.0 g, 7.1 mmol) and purified by preparative HPLC (PrepHPLC Method T). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.89 (s, 1H), 8.74 (s, 1H),8.49 (d, J=2.0 Hz, 1H), 8.09 (s, 1H), 7.47-7.53 (m, 1H), 4.27-4.36 (m,3H), 3.87 (s, 3H), 3.82 (t, J=8.7 Hz, 1H), 3.50-3.56 (m, 1H), 1.75-1.80(m, 2H), 1.34 (dd, J=8.2, 16.3 Hz, 1H), 1.01-1.12 (m, 1H), 0.98 (t,J=7.3 Hz, 3H). LCMS m/z=347 [MH]⁺.

Example 50:4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(0.51 g, 31%) was prepared in an analogous manner to Example 33 using3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(4-(difluoromethoxy)-3-propoxyphenyl)pyridine(Preparation 21, 2.6 g, 4.50 mmol) and purified by preparative HPLC(Prep HPLC Method U). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.74 (d, J=2.1 Hz,1H), 8.72 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.00 (t, J=2.0 Hz, 1H), 7.45(d, J=1.6 Hz, 1H), 7.28-7.31 (m, 2H), 7.09 (t, J=74.5 Hz, 1H), 4.28 (t,J=8.3 Hz, 1H), 4.12 (t, J=6.4 Hz, 2H), 3.87 (t, J=9.1 Hz, 1H), 3.47-3.56(m, 1H), 1.73-1.82 (m, 2H), 1.29-1.35 (m, 1H), 1.12-1.19 (m, 1H), 1.01(t, J=7.5 Hz, 3H). LCMS m/z=382 [MH+H₂O]⁺.

Example 51:4-(6′-methoxy-5′-propoxy-[3,3′-bipyridin]-5-yl)-1,2-oxaborolan-2-ol

4-(6′-methoxy-5′-propoxy-[3,3′-bipyridin]-5-yl)-1,2-oxaborolan-2-ol wasprepared (720 mg, 25%) in an analogous manner to Example 33 using5′-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-6-methoxy-5-propoxy-3,3′-bipyridine(Preparation 23, 1.034 g, 1.9 mmol) and purified by preparative HPLC(Prep HPLC Method V). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.76 (d, J=2.2 Hz,1H), 8.72 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 8.01(t, J=2.2 Hz, 1H), 7.61 (d, J=2.2 Hz, 1H), 4.26-4.31 (m, 1H), 4.08 (t,J=6.6 Hz, 2H), 3.92 (s, 3H), 3.87 (t, J=9.1 Hz, 1H), 3.48-3.56 (m, 1H),1.73-1.82 (m, 2H), 1.28-1.35 (m, 1H), 1.13-1.21 (m, 1H), 1.00 (t, J=7.5Hz, 3H). LCMS m/z=329 [MH]⁺.

Example 52:4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol(182 mg, 43%) was prepared in an analogous manner to Example 33 using5-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-2-methylpyridine(Preparation 24, 700 mg, 1.29 mmol) and purified by preparative HPLC(Prep HPLC Method W). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.67 (s, 1H), 8.33(d, J=2.0 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 6.94(d, J=2.0 Hz, 1H), 6.88 (dd, J=2.0, 7.8 Hz, 1H), 4.24 (t, J=8.1 Hz, 1H),4.04 (q, J=6.9 Hz, 2H), 3.76-3.83 (m, 4H), 3.39-3.50 (m, 1H), 2.40 (s,3H), 1.24-1.36 (m, 4H), 1.01-1.10 (m, 1H). LCMS m/z=328 [MH]⁺.

Example 53:4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol

4-(5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridin-3-yl)-1,2-oxaborolan-2-ol(0.06 g, 33%) was prepared in an analogous manner to Example 33 using3-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-5-(3-ethoxy-4-methoxyphenyl)-4-methylpyridine(Preparation 35, 0.28 g, 0.51 mmol) and purified by preparative HPLC(Prep HPLC Method X). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H), 8.43(s, 1H), 8.21 (s, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H),6.82-6.85 (m, 1H), 4.24-4.28 (m, 1H), 4.03 (q, J=7.0 Hz, 2H), 3.90-3.95(m, 1H), 3.80 (s, 3H), 3.63-3.71 (m, 1H), 2.22 (s, 3H), 1.30-1.36 (m,4H), 1.04-1.10 (m, 1H). LCMS m/z=328 [MH]⁺.

Example 54:4-(2-(4-methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol

4-(2-(4-methoxy-3-propoxyphenyl)-6-methylpyrimidin-4-yl)-1,2-oxaborolan-2-ol(314 mg, 95%) was prepared in an analogous manner to Example 33 usingethyl2-(6-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)acetate(Preparation 28, 500 mg, 0.96 mmol) and purified by preparative HPLC(Prep HPLC Method Y). ¹H NMR (CD₃OD, 400 MHz): δ 8.03 (dd, J=2.0, 8.6Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.07 (s, 1H), 7.05 (d, J=8.3 Hz, 1H),4.17 (br s, 1H), 4.07 (t, J=6.5 Hz, 2H), 4.00 (br s, 1H), 3.91 (s, 2H),3.41 (br s, 1H), 2.52 (s, 2H), 1.84-1.89 (m, 2H), 1.29-1.38 (m, 1H),1.21-1.29 (m, 1H), 1.09 (t, J=7.3 Hz, 3H). LCMS m/z=343 [MH]⁺.

Example 55:4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol

4-(2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol(582 mg, 36%) was prepared in an analogous manner to Example 33 using4-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-2-(4-methoxy-3-propoxyphenyl)-6-(trifluoromethyl)pyrimidine(Preparation 25, 2.5 g, 4.09 mmol) and purified by preparative HPLC(Prep HPLC Method Z). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (s, 1H), 8.03(dd, J=2.0, 8.6 Hz, 1H), 7.95 (d, J=2.0 Hz, 1H), 7.77 (s, 1H), 7.13 (d,J=8.6 Hz, 1H), 4.32 (dd, J=7.4, 9.0 Hz, 1H), 3.98-4.09 (m, 3H), 3.86 (s,3H), 3.73-3.82 (m, 1H), 1.73-1.84 (m, 1H), 1.31-1.41 (m, 1H), 1.18-1.26(m, 2H), 1.01 (t, J=7.4 Hz, 3H). LCMS m/z=397 [MH]⁺.

Example 56:4-(6-(3-ethoxy-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol

4-(6-(3-ethoxy-4-methoxyphenyl)pyrazin-2-yl)-1,2-oxaborolan-2-ol (30 mg,7%) was prepared in an analogous manner to Example 33 using2-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-6-(3-ethoxy-4-methoxyphenyl)pyrazine(Preparation 26, 720 mg, 1.36 mmol) and purified by preparative HPLC(Prep HPLC Method AA). ¹H NMR (DMSO-d₆, 400 MHz): δ 9.06 (s, 1H), 8.67(s, 1H), 8.44 (s, 1H), 8.37-8.50 (m, 1H), 7.65-7.79 (m, 2H), 7.08 (d,J=8.8 Hz, 1H), 4.30 (t, J=8.2 Hz, 1H), 4.12 (q, J=6.9 Hz, 2H), 3.98 (dd,J=6.5, 8.9 Hz, 1H), 3.83 (s, 3H), 3.66-3.70 (m, 1H), 1.37 (t, J=7.0 Hz,3H), 1.27-1.34 (m, 1H), 1.14-1.22 (m, 1H). LCMS m/z=315 [MH]⁺.

Example 57:4-(6-(hydroxymethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol

4-(6-(hydroxymethyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidin-4-yl)-1,2-oxaborolan-2-ol(0.2 g, 38.4%) was prepared in an analogous manner to Example 33 using4-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-methoxy-3-propoxyphenyl)pyrimidine(Preparation 29, 1.0 g, 1.5 mmol) and purified by preparative HPLC (PrepHPLC Method BA). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H), 8.00 (dd,J=2.0, 8.0 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.52 (s, 1H), 7.27-7.31 (m,1H), 7.06 (d, J=8.5 Hz, 1H), 5.60-5.66 (m, 1H), 4.59 (d, J=6.0 Hz, 2H),4.31 (dd, J=7.0, 9.0 Hz, 1H), 3.96-4.04 (m, 2H), 3.83 (s, 3H), 3.57-3.65(m, 1H), 1.75-1.82 (m, 2H), 1.25-1.35 (m, 1H), 1.12-1.21 (m, 1H),0.96-1.07 (m, 3H). LCMS m/z=359 [MH]⁺.

Example 58:4-(2-(3-ethoxy-4-methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol

4-(2-(3-ethoxy-4-methoxyphenyl)thiazol-4-yl)-1,2-oxaborolan-2-ol(0.31 g,37%) was prepared in an analogous manner to Example 33 using4-(1-((tert-butyldimethylsilyl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-2-(3-ethoxy-4-methoxyphenyl)thiazole(Preparation 36, 1.42 g, 2.66 mmol) and purified by preparative HPLC(Prep HPLC Method CA). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.66 (br s, 1H),7.42-7.46 (m, 2H), 7.30 (s, 1H), 7.05 (d, J=8.3 Hz, 1H), 4.24-4.28 (m,1H), 4.09 (q, J=7.0 Hz, 2H), 3.90-3.95 (m, 1H), 3.82 (s, 3H), 3.55-3.63(m, 1H), 1.36 (t, J=7.0 Hz, 3H), 1.25-1.31 (m, 1H), 1.11-1.18 (m, 1H).LCMS m/z=320 [MH]⁺.

Example 59:(2R)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan-1-ol

To hexylene glycol (1.0 g, 8.46 mmol) was added(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 4, 0.051 g, 0.16 mmol) at about 20° C. The mixture was stirreduntil homogeneous to afford(2R)-2-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-3-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)propan-1-ol(5 wt % solution in hexylene glycol) as a mixture of diastereomers (1:1ratio). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.64 (d, J=2.2 Hz, 1H), 8.32 (d,J=1.9 Hz, 1H), 7.77 (t, J=2.2 Hz, 1H), 7.23 (s, 1H), 7.17-7.25 (m, 1H),7.06 (d, J=8.1 Hz, 1H), 4.61 (m, 1H), 4.02 (t, J=6.6 Hz, 2H), 3.97-4.07(m, 1H), 3.80 (s, 3H), 3.46-3.58 (m, 2H), 2.84-2.98 (m, 1H), 1.69-1.83(m, 3H), 1.14 (m, 1H), 1.02-1.09 (m, 1OH), 1.00 (t, J=7.4 Hz, 3H), 0.83(dd, J=9.0, 15.0 Hz, 1H). LCMS m/z=428 [MH]⁺.

The following compounds, Example 60-, were prepared similarly usingmethods described above. Examples containing an asterisk (*), designatesa single enantiomer obtained through chiral purification methods. Forthose examples characterized by HPLC retention time (RT), the analyticalHPLC methods are described.

Structure Example and No. Name Analytical Data 60

¹H NMR (DMSO-d₆, 400 MHz): δ 9.04 (d, J = 2.0 Hz, 1H), 8.71 (s, 1H),8.45 (d, J = 2.0 Hz, 1H), 8.22 (t, J = 2.2 Hz, 1H), 7.61 (d, J = 7.8 Hz,1H), 7.37 (d, J = 8.3 Hz, 1H), 4.36 (t, J = 6.6 Hz, 2H), 4.26-4.32 (m,1H), 3.80-3.88 (m, 4H), 3.45-3.58 (m, 1H), 1.75-1.84 (m, 2H), 1.33 (dd,J = 8.3, 16.1 Hz, 1H), 1.06-1.17 (m, 1H), 1.00 (t, J = 7.3 Hz, 3H). LCMSm/z = 329 [MH]⁺. Example 61

¹H NMR (DMSO-d₆, 400 MHz): δ 9.04 (d, J = 2.0 Hz, 1H), 8.71 (s, 1H),8.45 (d, J = 2.0 Hz, 1H), 8.22 (t, J = 2.2 Hz, 1H), 7.61 (d, J = 7.8 Hz,1H), 7.37 (d, J = 8.3 Hz, 1H), 4.36 (t, J = 6.6 Hz, 2H), 4.26-4.32 (m,1H), 3.80-3.88 (m, 4H), 3.45-3.58 (m, 1H), 1.75-1.84 (m, 2H), 1.33 (dd,J = 8.3, 16.1 Hz, 1H), 1.06-1.17 (m, 1H), 1.00 (t, J = 7.3 Hz, 3H). LCMSm/z = 329 [MH]⁺. RT [Analytical SFC Method I] = 4.57 min. 62

¹H NMR (DMSO-d₆, 400 MHz): δ 9.04 (d, J = 2.0 Hz, 1H), 8.71 (s, 1H),8.45 (d, J = 2.0 Hz, 1H), 8.22 (t, J = 2.2 Hz, 1H), 7.61 (d, J = 7.8 Hz,1H), 7.37 (d, J = 8.3 Hz, 1H), 4.36 (t, J = 6.6 Hz, 2H), 4.26-4.32 (m,1H), 3.80-3.88 (m, 4H), 3.45-3.58 (m, 1H), 1.75-1.84 (m, 2H), 1.33 (dd,J = 8.3, 16.1 Hz, 1H), 1.06-1.17 (m, 1H), 1.00 (t, J = 7.3 Hz, 3H). LCMSm/z = 329 [MH]⁺. RT [Analytical SFC Method I] = 4.98 min. 63

¹H NMR (DMSO-d₆, 400 MHz): δ 7.51 (br s, 1H), 7.46 (d, J = 7.8 Hz, 1H),7.35 (t, J = 7.8 Hz, 1H), 7.18-7.23 (m, 3H), 7.06 (d, J = 8.2 Hz, 1H),4.81-4.83 (m, 1H), 4.69- 4.71 (m, 1H), 4.36-4.38 (m, 1H), 4.24- 4.30 (m,2H), 3.79-3.83 (m, 4H), 3.42- 3.51 (m, 1H), 1.26-1.32 (m, 1H), 1.05-1.12 (m, 1H). LCMS m/z = 331 [MH]⁺. 64

¹H NMR (DMSO-d₆, 400 MHz): δ 8.59 (br s, 1H), 7.69 (d, J = 2.0 Hz, 1H),7.57- 7.66 (m, 2H), 7.11 (s, 1H), 7.00-7.06 (m, 1H), 5.41 (br s, 1H),4.56 (s, 2H), 4.28 (dd, J = 7.3, 8.78 Hz, 1H), 3.94-4.03 (m, 3H), 3.80(s, 3H), 3.52-3.62 (m, 1H), 1.70-1.82 (m, 2H), 1.13-1.30 (m, 2H), 1.00(t, J = 7.5 Hz, 3H). LCMS m/z = 376 [MH + H₂O]⁺. 65

¹H NMR (DMSO-d₆, 400 MHz): δ 8.59 (s, 1H), 7.70-7.75 (m, 3H), 7.62 (dd,J = 2.0, 8.3 Hz, 1H), 7.10-7.20 (m, 1H), 7.03 (d, J = 8.6 Hz, 1H), 4.90(t, J = 5.9 Hz, 1H), 4.29 (t, J = 8.2 Hz, 1H), 3.99 (dd, J = 7.0, 8.9Hz, 1H), 3.79 (s, 3H), 3.56-3.63 (m, 1H), 1.87-2.04 (m, 2H), 1.68-1.81(m, 4H), 1.59 (br s, 2H), 1.16-1.30 (m, 2H). LCMS m/z = 372 [MH + H₂O]⁺.66

LCMS m/z = 354 [MH]⁺. RT [Analytical SFC Method V] = 3.60 min. 67

LCMS m/z = 354 [M + H]⁺. RT [Analytical SFC Method V] = 3.93 min. 68

¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (s, 1H), 8.70 (d, J = 2.0 Hz, 1H),8.42 (d, J = 2.0 Hz, 1H), 7.92 (t, J = 2.0 Hz, 1H), 7.31 (dd, J = 2.3,8.3 Hz, 1H), 7.22 (d, J = 2.5 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 5.44-5.53 (m, 1H), 4.27 (t, J = 8.3 Hz, 1H), 3.86 (t, J = 9.0 Hz, 1H), 3.81(s, 3H), 3.47 (dd, J = 3.8, 7.8 Hz, 5H), 1.31 (dd, J = 8.3, 16.3 Hz,1H), 1.11 1.19 (m, 1H). LCMS m/z = 358 [MH]⁺. 69

¹H NMR (MeOD-d₃, 400 MHz): δ 8.40 (d, J = 2.0 Hz, 1H), 8.31 (d, J = 2.5Hz, 1H), 7.69 (t, J = 2.0 Hz, 1H), 6.92 (s, 1H), 6.80 (s, 1H), 4.06 (q,J = 6.9 Hz, 2H), 3.83-3.90 (m, 4H), 3.33-3.40 (m, 1H), 2.21 (s, 3H),1.39 (t, J = 6.9 Hz, 3H), 1.16-1.33 (m, 2H) LCMS m/z = 328 [MH]⁺. 70

¹H NMR (DMSO-d₆, 400 MHz): δ 8.69 (br s, 1H), 8.31-8.49 (m, 2H), 7.66(br s, 1H), 6.91 (br s, 1H), 6.81 (br s, 1H), 4.27 (br s, 1H), 4.01 (d,J = 5.9 Hz, 2H), 3.73- 3.90 (m, 4H), 3.49 (br s, 1H), 2.18 (br s, 3H),1.30 (br s, 3H), 0.99-1.16 (m, 2H). LCMS m/z = 346 [MH + H₂O]⁺. RT[Analytical SFC Method L] = 2.67 min. 71

¹H NMR (DMSO-d₆, 400 MHz): δ 8.69 (br s, 1H), 8.31-8.49 (m, 2H), 7.66(br s, 1H), 6.91 (br s, 1H), 6.81 (br s, 1H), 4.27 (br s, 1H), 4.01 (d,J = 5.9 Hz, 2H), 3.73- 3.90 (m, 4H), 3.49 (br s, 1H), 2.18 (br s, 3H),1.30 (br s, 3H), 0.99-1.16 (m, 2H). LCMS m/z = 327 [MH]⁺. RT [AnalyticalSFC Method L] = 2.91 min. 72

¹H NMR (DMSO-d, 400 MHz): δ 7.58 (dd, J = 1.8, 8.4 Hz, 1H), 7.46 (d, J =1.71 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 4.27-4.37 (m, 1H), 4.07-4.16 (m,3H), 3.85 (s, 3H), 3.76-3.83 (m, 1H), 1.23- 1.43 (m, 5H). LCMS m/z =321.1 [MH]⁺. 73

¹H NMR (DMSO-d₆, 400 MHz): δ 8.70 (s, 1H), 8.54 (s, 1H), 8.48 (d, J =2.0 Hz, 1H), 7.81 (d, J = 1.5 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.01(dd, J = 1.0, 8.8 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 4.06 (q, J = 7.3Hz, 2H), 3.80-3.90 (m, 4H), 3.44-3.58 (m, 1H), 1.24-1.39 (m, 4H),0.99-1.16 (m, 1H). LCMS m/z = 332 [MH]⁺. RT [Analytical SFC Method GA] =6.58 min. 74

¹H NMR (DMSO-d, 400 MHz): δ 8.70 (s, 1H), 8.54 (s, 1H), 8.48 (d, J = 2.0Hz, 1H), 7.81 (d, J = 1.5 Hz, 1H), 7.26 (t, J = 8.8 Hz, 1H), 7.01 (dd, J= 1.0, 8.8 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 4.06 (q, J = 7.3 Hz, 2H),3.80-3.90 (m, 4H), 3.44-3.58 (m, 1H), 1.24-1.39 (m, 4H), 0.99-1.16 (m,1H). LCMS m/z = 332 [MH]⁺. 75

¹H NMR (DMSO-d₆, 400 MHz): δ 7.48 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H),7.34 (t, J = 7.6 Hz, 1H), 7.14-7.24 (m, 3H), 7.00-7.06 (m, 1H),4.61-4.71 (m, 1H), 4.22-4.29 (m, 1H), 3.77-3.85 (m, 3H), 3.37-3.53 (m,1H), 1.22-1.31 (m, 7H), 0.99-1.12 (m, 3H). LCMS m/z = 327 [MH]⁺. 76

¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H), 8.00 (dd, J = 2.0, 8.0 Hz,1H), 7.96 (d, J = 2.0 Hz, 1H), 7.52 (s, 1H), 7.27- 7.31 (m, 1H), 7.06(d, J = 8.5 Hz, 1H), 5.60-5.66 (m, 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.31(dd, J = 7.0, 9.0 Hz, 1H), 3.96- 4.04 (m, 2H), 3.83 (s, 3H), 3.57-3.65(m, 1H), 1.75-1.82 (m, 2H), 1.25-1.35 (m, 1H), 1.12-1.21 (m, 1H),0.96-1.07 (m, 3H). LCMS m/z = 359 [MH]⁺. [α]²⁰ _(D) −10.0 (c = 0.1,EtOH). 77

¹H NMR (DMSO-d₆, 400 MHz): δ 8.65 (s, 1H), 7.50 (s, 1H), 7.45 (d, J =7.6 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.18(s, 1H), 7.16 (d, J = 1.71 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 4.26 (t, J= 8.3 Hz, 1H), 4.10 (q, J = 6.9 Hz, 2H), 3.77-3.84 (m, 4H), 3.42-3.49(m, 1H), 1.35 (t, J = 7.0 Hz, 3H), 1.28 (dd, J = 8.2, 16.3 Hz, 1H), 1.08(dd, J = 10.0, 16.4 Hz, 1H). LCMS/m/z = 313 [MH]⁺. 78

¹H NMR (DMSO-d₆, 400 MHz): δ 8.73 (s, 1H), 8.70 (d, J = 2.0 Hz, 1H),8.43 (d, J = 2.0 Hz, 1H), 7.93 (t, J = 2.0 Hz, 1H), 7.36 (d, J = 2.0 Hz,1H), 7.30-7.34 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 5.30 (br s, 1H), 4.27(t, J = 8.3 Hz, 1H), 3.86 (t, J = 9.0 Hz, 1H), 3.81 (s, 3H), 3.46-3.55(m, 1H), 3.13 (dd, J = 4.8, 11.8 Hz, 1H), 2.85-3.00 (m, 3H), 2.27-2.34(m, 1H), 1.90-2.00 (m, 1H), 1.31 (dd, J = 8.3, 16.3 Hz, 1H), 1.14 (dd, J= 10.3, 16.3 Hz, 1H). LCMS m/z = 372 [MH]⁺. 79

¹H NMR (DMSO-d₆, 400 MHz): δ 8.73 (s, 1H), 8.70 (d, J = 2.0 Hz, 1H),8.43 (d, J = 2.0 Hz, 1H), 7.93 (t, J = 2.0 Hz, 1H), 7.36 (d, J = 2.0 Hz,1H), 7.30-7.34 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 5.30 (br s, 1H), 4.27(t, J = 8.3 Hz, 1H), 3.86 (t, J = 9.0 Hz, 1H), 3.81 (s, 3H), 3.46-3.55(m, 1H), 3.13 (dd, J = 4.8, 11.8 Hz, 1H), 2.85-3.00 (m, 3H), 2.27-2.34(m, 1H), 1.90-2.00 (m, 1H), 1.31 (dd, J = 8.3, 16.3 Hz, 1H), 1.14 (dd, J= 10.3, 16.3 Hz, 1H). LCMS m/z = 372.3 [MH]⁺. RT [Analytical SFC MethodEA] = 3.30 min. 80

¹H NMR (DMSO-d₆, 400 MHz): δ 8.73 (s, 1H), 8.70 (d, J = 2.0 Hz, 1H),8.43 (d, J = 2.0 Hz, 1H), 7.93 (t, J = 2.0 Hz, 1H), 7.36 (d, J = 2.0 Hz,1H), 7.30-7.34 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 5.30 (br s, 1H), 4.27(t, J = 8.3 Hz, 1H), 3.86 (t, J = 9.0 Hz, 1H), 3.81 (s, 3H), 3.46-3.55(m, 1H), 3.13 (dd, J = 4.8, 11.8 Hz, 1H), 2.85-3.00 (m, 3H), 2.27-2.34(m, 1H), 1.90-2.00 (m, 1H), 1.31 (dd, J = 8.3, 16.3 Hz, 1H), 1.14 (dd, J= 10.3, 16.3 Hz, 1H). LCMS m/z = 372.1 [MH]⁺. RT [Analytical SFC MethodEA] = 4.18 min. 81

¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H), 8.54 (t, J = 2.0 Hz, 1H),8.48 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.26 (t, J = 8.7 Hz,1H), 7.01 (dd, J = 1.5, 8.8 Hz, 1H), 4.24-4.32 (m, 1H), 3.97 (t, J = 6.6Hz, 2H), 3.87 (s, 3H), 3.80-3.86 (m, 1H), 3.44-3.57 (m, 1H), 1.63-1.72(m, 2H), 1.31 (dd, J = 8.2, 16.3 Hz, 1H), 1.10 (dd, J = 10.3, 16.1 Hz,1H), 0.98 (t, J = 7.3 Hz, 3H). LCMS m/z = 346 [MH]⁺. 82

¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H), 8.54 (t, J = 2.0 Hz, 1H),8.48 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.26 (t, J = 8.7 Hz,1H), 7.01 (dd, J = 1.5, 8.8 Hz, 1H), 4.24-4.32 (m, 1H), 3.97 (t, J = 6.6Hz, 2H), 3.87 (s, 3H), 3.80-3.86 (m, 1H), 3.44-3.57 (m, 1H), 1.63-1.72(m, 2H), 1.31 (dd, J = 8.2, 16.3 Hz, 1H), 1.10 (dd, J = 10.3, 16.1 Hz,1H), 0.98 (t, J = 7.3 Hz, 3H). LCMS m/z = 372 [MH]⁺. RT [Analytical SFCMethod E] = 4.76 min. 83

¹H NMR (DMSO-d₆, 400 MHz): δ 8.68 (s, 1H), 8.00 (dd, J = 2.0, 8.3 Hz,1H), 7.97 (d, J = 2.0 Hz, 1H), 7.32 (s, 1H), 7.07 (d, J = 8.3 Hz, 1H),5.57 (d, J = 4.9 Hz, 1H), 4.65-4.75 (m, 1H), 4.30 (dd, J = 7.3, 9.3 Hz,1H), 3.96-4.03 (m, 3H), 3.83 (s, 3H), 3.61 (s, 1H), 1.71-1.83 (m, 2H),1.43 (d, J = 6.4 Hz, 3H), 1.27 (dd, J = 1.5, 8.3 Hz, 1H), 1.11-1.20 (m,1H), 1.01 (t, J = 7.6 Hz, 3H). LCMS m/z = 391 [MH + H₂O]⁺. RT[Analytical SFC Method E] = 4.07 min. 84

¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H),7.04 (d, J = 7.8 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.84 (dd, J = 2.0,8.3 Hz, 1H), 4.26 (dd, J = 7.3, 8.8 Hz, 1H), 3.89-3.97 (m, 3H), 3.80 (s,3H), 3.67 (t, J = 8.1 Hz, 1H), 2.21 (s, 3H), 1.68-1.77 (m, 2H), 1.33(dd, J = 8.3, 16.1 Hz, 1H), 1.08 (dd, J = 8.6, 16.4 Hz, 1H), 0.97 (t, J= 7.3 Hz, 3H). LCMS m/z = 342 [MH]⁺. 85

¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H),7.04 (d, J = 7.8 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.84 (dd, J = 2.0,8.3 Hz, 1H), 4.26 (dd, J = 7.3, 8.8 Hz, 1H), 3.89-3.97 (m, 3H), 3.80 (s,3H), 3.67 (t, J = 8.1 Hz, 1H), 2.21 (s, 3H), 1.68-1.77 (m, 2H), 1.33(dd, J = 8.3, 16.1 Hz, 1H), 1.08 (dd, J = 8.6, 16.4 Hz, 1H), 0.97 (t, J= 7.3 Hz, 3H). LCMS m/z = 342 [MH]⁺. [α]²⁰ _(D) +14.7 (c = 0.1, EtOH).86

¹H NMR (DMSO-d₆, 400 MHz): δ 8.58 (s, 1H), 7.85 (t, J = 7.7 Hz, 1H),7.60 (d, J = 7.8 Hz, 1H), 7.56-7.52 (m, 1H), 7.44- 7.49 (m, 1H), 7.32(d, J = 7.6 Hz, 1H), 4.24-4.31 (m, 1H), 4.06-4.14 (m, 3H), 3.91 (s, 3H),3.60-3.68 (m, 1H), 1.70- 1.79 (m, 2H), 1.20-1.37 (m, 2H), 1.02 (t, J =7.5 Hz, 3H). LCMS m/z = 353 [MH]⁺. 87

¹H NMR (DMSO-d₆, 400 MHz): δ 8.58 (s, 1H), 7.85 (t, J = 7.7 Hz, 1H),7.60 (d, J = 7.8 Hz, 1H), 7.56-7.52 (m, 1H), 7.44- 7.49 (m, 1H), 7.32(d, J = 7.6 Hz, 1H), 4.24-4.31 (m, 1H), 4.06-4.14 (m, 3H), 3.91 (s, 3H),3.60-3.68 (m, 1H), 1.70- 1.79 (m, 2H), 1.20-1.37 (m, 2H), 1.02 (t, J =7.5 Hz, 3H). LCMS m/z = 353.3 [MH]⁺. RT [Analytical SFC Method M] = 5.79min. 88

1H NMR (DMSO-d₆, 400 MHz): δ 8.66 (s, 1H), 7.44-7.49 (m, 2H), 7.35 (m,1H), 7.16-7.22 (m, 3H), 7.02 (d, J = 8.0 Hz, 1H), 4.26 (t, J = 8.0 Hz,1H), 4.01 (t, J = 6.8 Hz, 2H), 3.79-3.83 (m, 4H), 3.34-3.51 (m, 1H),1.73-1.79 (m, 2H), 1.25-1.29 (m, 1H), 1.07-1.11 (m, 1H), 0.99 (t, J =7.6 Hz, 3H). LCMS m/z = 327 [MH]⁺. 89

1H NMR (DMSO-d₆, 400 MHz): δ 8.66 (s, 1H), 7.44-7.49 (m, 2H), 7.35 (m,1H), 7.16-7.22 (m, 3H), 7.02 (d, J = 8.0 Hz, 1H), 4.26 (t, J = 8.0 Hz,1H), 4.01 (t, J = 6.8 Hz, 2H), 3.79-3.83 (m, 4H), 3.34-3.51 (m, 1H),1.73-1.79 (m, 2H), 1.25-1.29 (m, 1H), 1.07-1.11 (m, 1H), 0.99 (t, J =7.6 Hz, 3H). LCMS m/z = 327 [MH]⁺. RT [Analytical SFC Method N] = 3.76min. 90

1H NMR (DMSO-d₆, 400 MHz): δ 8.66 (s, 1H), 7.44-7.49 (m, 2H), 7.35 (m,1H), 7.16-7.22 (m, 3H), 7.02 (d, J = 8.0 Hz, 1H), 4.26 (t, J = 8.0 Hz,1H), 4.01 (t, J = 6.8 Hz, 2H), 3.79-3.83 (m, 4H), 3.34-3.51 (m, 1H),1.73-1.79 (m, 2H), 1.25-1.29 (m, 1H), 1.07-1.11 (m, 1H), 0.99 (t, J =7.6 Hz, 3H). LCMS m/z = 327 [MH]⁺. RT [Analytical SFC Method N] = 3.97min. 91

¹H NMR (DMSO-d₆, 400 MHz): δ 8.66 (s, 1H), 7.62 (d, J = 7.0 Hz, 1H),7.41 (s, 1H), 7.05-7.10 (m, 1H), 4.26 (dd, J = 7.5, 8.5 Hz, 1H), 4.05(q, J = 6.9 Hz, 2H), 3.93 (dd, J = 7.5, 9.0 Hz, 1H), 3.83 (s, 3H),3.57-3.66 (m, 1H), 1.34 (t, J = 7.0 Hz, 3H), 1.25-1.32 (m, 1H),1.12-1.20 (m, 1H). LCMS m/z = 338 [MH]⁺. 92

¹H NMR (DMSO-d₆, 400 MHz): δ 8.66 (s, 1H), 7.62 (d, J = 7.0 Hz, 1H),7.41 (s, 1H), 7.05-7.10 (m, 1H), 4.26 (dd, J = 7.5, 8.5 Hz, 1H), 4.05(q, J = 6.9 Hz, 2H), 3.93 (dd, J = 7.5, 9.0 Hz, 1H), 3.83 (s, 3H),3.57-3.66 (m, 1H), 1.34 (t, J = 7.0 Hz, 3H), 1.25-1.32 (m, 1H),1.12-1.20 (m, 1H). LCMS m/z = 338 [MH]⁺. RT [Analytical SFC Method O] =4.13 min. [α]²⁰ _(D) −37.9 (c = 0.1, EtOH). 93

¹H NMR (DMSO-d₆, 400 MHz): δ 8.67 (br s, 1H), 8.30 (s, 1H), 8.18 (s,1H), 8.10- 8.15 (m, 1H), 7.39-7.45 (m, 1H), 7.34- 7.38 (m, 1H),5.56-5.63 (m, 1H), 4.26- 4.32 (m, 1H), 3.89 (s, 3H), 3.80 (t, J = 8.6Hz, 1H), 3.48-3.55 (m, 1H), 2.04-2.15 (m, 2H), 1.60-1.85 (m, 6H), 1.33(dd, J = 8.3, 16.1 Hz, 1H), 0.99-1.08 (m, 1H). LCMS m/z = 355 [MH]⁺. 94

¹H NMR (DMSO-d₆, 400 MHz): δ 8.70 (d, J = 2.5 Hz, 1H), 8.48 (d, J = 2.0Hz, 1H), 8.26-8.32 (m, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.37-7.43 (m, 1H),7.05 (d, J = 9.0 Hz, 1H), 4.19-4.34 (m, 1H), 4.09 (td, J = 3.1, 9.9 Hz,2H), 3.87-3.95 (m, 3H), 3.72- 3.83 (m, 1H), 3.46-3.55 (m, 1H), 1.26-1.37 (m, 4H), 1.00-1.13 (m, 1H). LCMS m/z = 382 [MH]⁺. 95

¹H NMR (DMSO-d₆, 400 MHz): δ 8.70 (d, J = 2.5 Hz, 1H), 8.48 (d, J = 2.0Hz, 1H), 8.26-8.32 (m, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.37-7.43 (m, 1H),7.05 (d, J = 9.0 Hz, 1H), 4.19-4.34 (m, 1H), 4.09 (td, J = 3.1, 9.9 Hz,2H), 3.87-3.95 (m, 3H), 3.72- 3.83 (m, 1H), 3.46-3.55 (m, 1H), 1.26-1.37 (m, 4H), 1.00-1.13 (m, 1H). LCMS m/z = 382 [MH]⁺. RT [AnalyticalSFC Method E] = 3.14 min. 96

¹H NMR (DMSO-d₆, 400 MHz): δ 8.68- 8.75 (m, 2H), 8.42 (d, J = 1.5 Hz,1H), 7.93 (s, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 1.8, 8.3 Hz,1H), 7.04 (d, J = 8.5 Hz, 1H), 4.27 (t, J = 8.3 Hz, 1H), 4.13 (q, J =6.9 Hz, 2H), 4.06 (q, J = 7.0 Hz, 2H), 3.86 (t, J = 8.8 Hz, 1H), 3.45-3.54 (m, 1H), 1.26-1.39 (m, 7H), 1.14 (dd, J = 10.5, 16.1 Hz, 1H). LCMSm/z = 328 [MH]⁺. 97

¹H NMR (DMSO-d₆, 400 MHz): δ 8.68- 8.75 (m, 2H), 8.42 (d, J = 1.5 Hz,1H), 7.93 (s, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 1.8, 8.3 Hz,1H), 7.04 (d, J = 8.5 Hz, 1H), 4.27 (t, J = 8.3 Hz, 1H), 4.13 (q, J =6.9 Hz, 2H), 4.06 (q, J = 7.0 Hz, 2H), 3.86 (t, J = 8.8 Hz, 1H), 3.45-3.54 (m, 1H), 1.26-1.39 (m, 7H), 1.14 (dd, J = 10.5, 16.1 Hz, 1H). LCMSm/z = 345 [MH + H₂O]⁺. RT [Analytical SFC Method D] = 5.73 min. 98

¹H NMR (DMSO-d₆, 400 MHz): δ 8.68- 8.75 (m, 2H), 8.42 (d, J = 1.5 Hz,1H), 7.93 (s, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 1.8, 8.3 Hz,1H), 7.04 (d, J = 8.5 Hz, 1H), 4.27 (t, J = 8.3 Hz, 1H), 4.13 (q, J =6.9 Hz, 2H), 4.06 (q, J = 7.0 Hz, 2H), 3.86 (t, J = 8.8 Hz, 1H), 3.45-3.54 (m, 1H), 1.26-1.39 (m, 7H), 1.14 (dd, J = 10.5, 16.1 Hz, 1H). LCMSm/z = 328 [MH]⁺. RT [Analytical SFC Method D] = 5.37 min. 99

¹H NMR (DMSO-d₆, 400 MHz): δ 8.73 (s, 2H), 8.44-8.48 (m, 1H), 7.96 (s,1H), 7.28-7.33 (m, 1H), 7.26 (s, 1H), 7.19- 7.24 (m, 1H), 5.10 (t, J =5.5 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 3.83-3.91 (m, 1H), 3.49-3.57 (m,1H), 2.39 (s, 3H), 1.87-1.96 (m, 2H), 1.75 (d, J = 4.5 Hz, 4H),1.56-1.66 (m, 2H), 1.32 (dd, J = 8.3, 16.3 Hz, 1H), 1.10-1.19 (m, 1H).LCMS m/z = 370 [MH]⁺. 100

¹H NMR (DMSO-d₆, 400 MHz): δ 8.73 (s, 2H), 8.44-8.48 (m, 1H), 7.96 (s,1H), 7.28-7.33 (m, 1H), 7.26 (s, 1H), 7.19- 7.24 (m, 1H), 5.10 (t, J =5.5 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 3.83-3.91 (m, 1H), 3.49-3.57 (m,1H), 2.39 (s, 3H), 1.87-1.96 (m, 2H), 1.75 (d, J = 4.5 Hz, 4H),1.56-1.66 (m, 2H), 1.32 (dd, J = 8.3, 16.3 Hz, 1H), 1.10-1.19 (m, 1H).LCMS m/z = 388 [MH + H₂O]⁺. RT [Analytical SFC Method P] = 3.83 min. 101

¹H NMR (DMSO-d₆, 400 MHz): δ 8.73 (s, 2H), 8.44-8.48 (m, 1H), 7.96 (s,1H), 7.28-7.33 (m, 1H), 7.26 (s, 1H), 7.19- 7.24 (m, 1H), 5.10 (t, J =5.5 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 3.83-3.91 (m, 1H), 3.49-3.57 (m,1H), 2.39 (s, 3H), 1.87-1.96 (m, 2H), 1.75 (d, J = 4.5 Hz, 4H),1.56-1.66 (m, 2H), 1.32 (dd, J = 8.3, 16.3 Hz, 1H), 1.10-1.19 (m, 1H).LCMS m/z = 388 [MH + H₂O]⁺. RT [Analytical SFC Method P] = 4.17 min. 102

¹H NMR (DMSO-d₆, 400 MHz): δ 8.69 (br s, 1H), 7.99 (dd, J = 1.9, 8.4 Hz,1H), 7.95 (d, J = 1.8 Hz, 1H), 7.22 (s, 1H), 7.07 (d, J = 8.8 Hz, 1H),4.54 (s, 2H), 4.30 (dd, J = 7.5, 8.8 Hz, 1H), 3.96-4.03 (m, 3H), 3.83(s, 3H), 3.58-3.65 (m, 1H), 3.43 (s, 3H), 1.73-1.81 (m, 2H), 1.24- 1.34(m, 1H), 1.12-1.21 (m, 1H), 0.96- 1.06 (m, 3H). LCMS m/z = 391 [MH +H₂O]⁺. 103

¹H NMR (DMSO-d₆, 400 MHz): δ 8.69 (br s, 1H), 7.99 (dd, J = 1.9, 8.4 Hz,1H), 7.95 (d, J = 1.8 Hz, 1H), 7.22 (s, 1H), 7.07 (d, J = 8.8 Hz, 1H),4.54 (s, 2H), 4.30 (dd, J = 7.5, 8.8 Hz, 1H), 3.96-4.03 (m, 3H), 3.83(s, 3H), 3.58-3.65 (m, 1H), 3.43 (s, 3H), 1.73-1.81 (m, 2H), 1.24- 1.34(m, 1H), 1.12-1.21 (m, 1H), 0.96- 1.06 (m, 3H). LCMS m/z = 391 [MH +H₂O]⁺. RT [Analytical SFC Method Q] = 3.25 min. [α]²⁰ _(D) −38.3 (c =0.1, EtOH). 104

¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H), 8.70 (d, J = 1.5 Hz, 1H),8.42 (d, J = 1.5 Hz, 1H), 7.93 (t, J = 2.0 Hz, 1H), 7.28 (d, J = 2.0 Hz,1H), 7.23 (dd, J = 2.0, 8.0 Hz, 1H), 7.03-7.07 (m, 1H), 4.27 (t, J = 8.3Hz, 1H), 4.00-4.11 (m, 4H), 3.86 (t, J = 9.0 Hz, 1H), 3.45-3.55 (m, 1H),1.70- 1.80 (m, 3H), 1.27-1.37 (m, 3H), 1.10- 1.19 (m, 1H), 1.00 (t, J =7.5 Hz, 3H). LCMS m/z = 342 [MH]⁺. 105

¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H), 8.70 (d, J = 1.5 Hz, 1H),8.42 (d, J = 1.5 Hz, 1H), 7.93 (t, J = 2.0 Hz, 1H), 7.28 (d, J = 2.0 Hz,1H), 7.23 (dd, J = 2.0, 8.0 Hz, 1H), 7.03-7.07 (m, 1H), 4.27 (t, J = 8.3Hz, 1H), 4.00-4.11 (m, 4H), 3.86 (t, J = 9.0 Hz, 1H), 3.45-3.55 (m, 1H),1.70- 1.80 (m, 3H), 1.27-1.37 (m, 3H), 1.10- 1.19 (m, 1H), 1.00 (t, J =7.5 Hz, 3H). LCMS m/z = 342 [MH]⁺. RT [Analytical SFC Method R] = 3.48min. 106

¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H), 8.70 (d, J = 1.5 Hz, 1H),8.42 (d, J = 1.5 Hz, 1H), 7.93 (t, J = 2.0 Hz, 1H), 7.28 (d, J = 2.0 Hz,1H), 7.23 (dd, J = 2.0, 8.0 Hz, 1H), 7.03-7.07 (m, 1H), 4.27 (t, J = 8.3Hz, 1H), 4.00-4.11 (m, 4H), 3.86 (t, J = 9.0 Hz, 1H), 3.45-3.55 (m, 1H),1.70- 1.80 (m, 3H), 1.27-1.37 (m, 3H), 1.10- 1.19 (m, 1H), 1.00 (t, J =7.5 Hz, 3H). LCMS m/z = 342 [MH]⁺. RT [Analytical SFC Method R] = 2.25min. 107

¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (s, 1H), 8.56 (dd, J = 2.0, 8.8 Hz,1H), 8.48 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.25- 7.29 (m, 1H), 7.02(d, J = 8.8 Hz, 1H), 4.28 (t, J = 8.4 Hz, 1H), 3.81-3.87 (m, 7H),3.41-3.55 (m, 1H), 1.29-1.35 (m, 1H), 1.06-1.13 (m, 1H). LCMS m/z = 318[MH]⁺. 108

LCMS m/z = 332 [MH + H₂O]⁺. RT [Analytical SFC Method S] = 5.28 min. 109

LCMS m/z = 318 [MH]⁺. RT [Analytical SFC Method S] = 5.35 min. 110

LCMS m/z = 355 [MH]^(+.) 111

¹H NMR (DMSO-d₆, 400 MHz): δ 8.89 (s, 1H), 8.74 (s, 1H), 8.49 (d, J =2.0 Hz, 1H), 8.09 (s, 1H), 7.47-7.53 (m, 1H), 4.27-4.36 (m, 3H), 3.87(s, 3H), 3.82 (t, J = 8.7 Hz, 1H), 3.50-3.56 (m, 1H), 1.75- 1.80 (m,2H), 1.34 (dd, J = 8.2, 16.3 Hz, 1H), 1.01-1.12 (m, 1H), 0.98 (t, J =7.3 Hz, 3H). LCMS m/z = 346 [MH]⁺. [α]²⁰ _(D) −17.7 (c = 0.15, EtOH).112

¹H NMR (DMSO-d₆, 400 MHz): δ 8.74 (d, J = 2.5 Hz, 1H), 8.73 (s, 1H),8.46 (d, J = 2.0 Hz, 1H), 7.98 (t, J = 2.0 Hz, 1H), 7.30-7.34 (m, 1H),7.26 (d, J = 1.5 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.28 (t, J = 8.3 Hz,1H), 4.11 (t, J = 6.3 Hz, 2H), 3.87 (t, J = 9.0 Hz, 1H), 3.46-3.57 (m,1H), 2.41 (s, 3H), 1.71-1.82 (m, 2H), 1.27- 1.36 (m, 1H), 1.11-1.20 (m,1H), 1.03 (t, J = 7.5 Hz, 3H). LCMS m/z = 344 [MH]⁺. 113

¹H NMR (DMSO-d₆, 400 MHz): δ 8.74 (d, J = 2.5 Hz, 1H), 8.73 (s, 1H),8.46 (d, J = 2.0 Hz, 1H), 7.98 (t, J = 2.0 Hz, 1H), 7.30-7.34 (m, 1H),7.26 (d, J = 1.5 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.28 (t, J = 8.3 Hz,1H), 4.11 (t, J = 6.3 Hz, 2H), 3.87 (t, J = 9.0 Hz, 1H), 3.46-3.57 (m,1H), 2.41 (s, 3H), 1.71-1.82 (m, 2H), 1.27- 1.36 (m, 1H), 1.11-1.20 (m,1H), 1.03 (t, J = 7.5 Hz, 3H). LCMS m/z = 343 [MH]⁺. RT = 5.23 min. 114

¹H NMR (DMSO-d₆, 400 MHz): δ 8.74 (d, J = 2.5 Hz, 1H), 8.73 (s, 1H),8.46 (d, J = 2.0 Hz, 1H), 7.98 (t, J = 2.0 Hz, 1H), 7.30-7.34 (m, 1H),7.26 (d, J = 1.5 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.28 (t, J = 8.3 Hz,1H), 4.11 (t, J = 6.3 Hz, 2H), 3.87 (t, J = 9.0 Hz, 1H), 3.46-3.57 (m,1H), 2.41 (s, 3H), 1.71-1.82 (m, 2H), 1.27- 1.36 (m, 1H), 1.11-1.20 (m,1H), 1.03 (t, J = 7.5 Hz, 3H). LCMS m/z = 343 [MH]⁺. RT = 5.63 min. 115

¹H NMR (DMSO-d₆, 400 MHz): δ 9.06 (s, 1H), 8.67 (s, 1H), 8.44 (s, 1H),7.73 (br s, 2H), 7.08 (d, J = 8.8 Hz, 1H), 4.30 (t, J = 8.2 Hz, 1H),3.94-4.06 (m, 3H), 3.83 (s, 3H), 3.61-3.74 (m, 1H), 1.71-1.83 (m, 2H),1.26-1.36 (m, 1H), 1.14-1.22 (m, 1H), 1.00 (t, J = 7.3 Hz, 3H). LCMS m/z= 329 [M + H]⁺. 116

¹H NMR (DMSO-d₆, 400 MHz): δ 8.65 (s, 1H), 7.36-7.40 (m, 2H), 7.26-7.32(m, 2H), 7.16 (t, J = 8.4 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 4.25 (t, J= 8.0 Hz, 1H), 3.96 (t, J = 4.2 Hz, 2H), 3.86 (s, 3H), 3.79 (t, J = 8.8Hz, 1H), 3.34-3.49 (m, 1H), 1.65- 1.71 (m, 2H), 1.26-1.28 (m, 1H), 1.02-1.08 (m, 1H), 0.98 (t, J = 8.0 Hz, 3H). LCMS m/z = 343 [MH]⁻. 117

¹H NMR (DMSO-d₆, 400 MHz): δ 7.47 (d, J = 8.8 Hz, 1H), 7.44 (s, 1H),7.41 (d, J = 7.2 Hz, 1H), 7.32-7.37 (m, 2H), 7.29 (d, J = 8.6 Hz, 1H),4.23-4.29 (m, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.81 (t, J = 8.8 Hz, 1H),1.29 (dd, J = 8.4, 16.2 Hz, 1H), 1.08 (dd, J = 10.0, 16.2 Hz, 1H). LCMSm/z = 324 [MH]⁺. 118

¹H NMR (DMSO-d₆, 400 MHz): δ 7.47 (d, J = 8.8 Hz, 1H), 7.44 (s, 1H),7.41 (d, J = 7.2 Hz, 1H), 7.32-7.37 (m, 2H), 7.29 (d, J = 8.6 Hz, 1H),4.23-4.29 (m, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.81 (t, J = 8.8 Hz, 1H),1.29 (dd, J = 8.4, 16.2 Hz, 1H), 1.08 (dd, J = 10.0, 16.2 Hz, 1H). LCMSm/z = 339 [MH]⁺. 119

¹H NMR (DMSO-d₆, 400 MHz): δ 7.47 (d, J = 8.8 Hz, 1H), 7.44 (s, 1H),7.41 (d, J = 7.2 Hz, 1H), 7.32-7.37 (m, 2H), 7.29 (d, J = 8.6 Hz, 1H),4.23-4.29 (m, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.81 (t, J = 8.8 Hz, 1H),1.29 (dd, J = 8.4, 16.2 Hz, 1H), 1.08 (dd, J = 10.0, 16.2 Hz, 1H). LCMSm/z = 339.1 [MH]⁺. RT [Analytical SFC Method T] = 4.71 min. 120

¹H NMR (DMSO-d₆, 400 MHz): δ 8.68 (s, 1H), 8.13 (s, 1H), 8.02 (d, J =7.6 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.48(t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 6.27 (s, 1H), 4.97 (s,2H), 4.47 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 1.39 (t, J = 6.8 Hz, 3H).LCMS m/z = 312 [MH]⁺. 121

¹H NMR (DMSO-d₆, 400 MHz): δ 8.65 (s, 1H), 7.88 (s, 1H), 7.83 (d, J =7.6 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.32-7.36 (m, 2H), 7.24 (d, J =7.2 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 4.27 (t, J = 8.0 Hz, 1H), 3.82(m, 4H), 3.43-3.51 (m, 1H) 1.38 (t, J = 6.8 Hz, 3H), 1.30 (q, J = 8.0Hz, 1H), 1.03-1.10 (m, 1H). LCMS m/z = 314 [MH]⁺. 122

¹H NMR (DMSO-d₆, 400 MHz): δ 8.67 (br s, 1H), 8.33 (s, 1H), 8.12-8.27(m, 2H), 7.31-7.50 (m, 2H), 4.24-4.34 (m, 1H), 4.06 (s, 3H), 3.90 (s,3H), 1.32 (br dd, J = 8.4, 16.2 Hz, 1H), 1.04 (br dd, J = 9.6, 16.1 Hz,1H). LCMS m/z = 317 [MH]⁺. 123

RT [Analytical SFC Method U] = 1.64 min. 124

¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (s, 1H), 8.03 (dd, J = 2.0, 8.6 Hz,1H), 7.95 (d, J = 2.0 Hz, 1H), 7.77 (s, 1H), 7.13 (d, J = 8.6 Hz, 1H),4.32 (dd, J = 7.4, 9.0 Hz, 1H), 3.98-4.09 (m, 3H), 3.86 (s, 3H),3.73-3.82 (m, 1H), 1.73-1.84 (m, 1H), 1.31-1.41 (m, 1H), 1.18-1.26 (m,2H), 1.01 (t, J = 7.4 Hz, 3H). LCMS m/z = 397 [MH + H₂O]⁺. [α]²⁰ _(D)+19.4 (c = 0.1, EtOH). 125

¹H NMR (DMSO-d₆, 400 MHz): δ 9.05 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H),7.70-7.73 (m, 2H), 7.05-7.10 (m, 1H), 4.92 (t, J = 6.1 Hz, 1H), 4.31(dd, J = 7.3, 9.3 Hz, 1H), 3.99 (dd, J = 6.6, 9.0 Hz, 1H), 3.81 (s, 3H),3.64-3.72 (m, 1H), 1.94 (d, J = 6.4 Hz, 2H), 1.68-1.81 (m, 4H),1.55-1.64 (m, 2H), 1.27-1.36 (m, 1H), 1.14-1.23 (m, 1H). LCMS m/z = 355[MH]⁺. 126

¹H NMR (DMSO-d₆, 400 MHz): δ 9.05 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H),7.70-7.73 (m, 2H), 7.05-7.10 (m, 1H), 4.92 (t, J = 6.1 Hz, 1H), 4.31(dd, J = 7.3, 9.3 Hz, 1H), 3.99 (dd, J = 6.6, 9.0 Hz, 1H), 3.81 (s, 3H),3.64-3.72 (m, 1H), 1.94 (d, J = 6.4 Hz, 2H), 1.68-1.81 (m, 4H),1.55-1.64 (m, 2H), 1.27-1.36 (m, 1H), 1.14-1.23 (m, 1H). LCMS m/z = 355[MH]⁺. RT [Analytical SFC Method C] = 7.2 min. 127

¹H NMR (DMSO-d₆, 400 MHz): δ 8.59 (s, 1H), 7.70-7.76 (m, 3H), 7.64 (d, J= 8.3 Hz, 1H), 7.16 (dd, J = 2.8, 5.3 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H),4.29 (t, J = 8.1 Hz, 1H), 3.94-4.05 (m, 3H), 3.81 (s, 3H), 3.55-3.63 (m,1H), 1.72-1.84 (m, 2H), 1.22-1.31 (m, 1H), 1.14-1.21 (m, 1H), 1.01 (t, J= 7.5 Hz, 3H). LCMS m/z = 346 [MH]⁺. 128

¹H NMR (DMSO-d₆, 400 MHz): δ 8.59 (s, 1H), 7.70-7.76 (m, 3H), 7.64 (d, J= 8.3 Hz, 1H), 7.16 (dd, J = 2.8, 5.3 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H),4.29 (t, J = 8.1 Hz, 1H), 3.94-4.05 (m, 3H), 3.81 (s, 3H), 3.55-3.63 (m,1H), 1.72-1.84 (m, 2H), 1.22-1.31 (m, 1H), 1.14-1.21 (m, 1H), 1.01 (t, J= 7.5 Hz, 3H). LCMS m/z = 328 [MH]⁺. [α]²⁰ _(D) −39.5 (c = 3.8, EtOH).129

¹H NMR (DMSO-d₆, 400 MHz): δ 7.71 (s, 1H), 7.62 (d, J = 7.2 Hz, 1H),7.51-7.53 (m, 1H), 7.44-7.48 (m, 1H), 7.21-7.24 (m, 2H), 7.04 (d, J =8.0 Hz, 1H), 6.27 (s, 1H), 4.94-4.98 (m, 3H), 3.79 (s, 3H), 1.87-1.94(m, 2H), 1.74-1.78 (m, 4H), 1.54-1.62 (m, 2H). LCMS m/z = 351 [MH]⁺. 130

¹H NMR (DMSO-d₆, 400 MHz): δ 7.48 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H),7.35 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.15-7.17 (m, 2H),7.02 (d, J = 8.8 Hz, 1H), 4.91-4.94 (m, 1H), 4.26 (t, J = 8.0 Hz, 1H),3.81 (t, J = 8.8 Hz, 1H), 3.77 (s, 3H), 3.42-3.51 (m, 1H), 1.88-1.92 (m,2H), 1.73-1.76 (m, 4H), 1.58 (m, 2H), 1.29 (q, J = 8.0 Hz, 1H),1.05-1.11 (m, 1H). LCMS m/z = 353 [MH]⁺. 131

¹H NMR (DMSO-d₆, 400 MHz): δ 8.61 (s, 1H), 7.68 (dd, J = 8.3, 11.8 Hz,1H), 7.58 (s, 1H), 7.50-7.55 (m, 1H), 7.27 (dd, J = 3.3, 8.3 Hz, 1H),7.07 (d, J = 8.5 Hz, 1H), 4.81-4.86 (m, 1H), 4.28 (dd, J = 7.5, 9.0 Hz,1H), 3.97 (dd, J = 7.3, 8.8 Hz, 1H), 3.81 (s, 3H), 3.58-3.66 (m, 1H),1.92 (d, J = 6.5 Hz, 2H), 1.68-1.80 (m, 4H), 1.59 (br s, 2H), 1.23-1.31(m, 1H), 1.12-1.20 (m, 1H). LCMS m/z = 344 [MH]⁺. 132

¹H NMR (DMSO-d₆, 400 MHz): δ 8.66 (br s, 1H), 7.98 (d, J = 2.0 Hz, 1H),7.96 (s, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.64 (s, 1H), 4.83-4.90 (m, 1H),4.26 (dd, J = 7.5, 9.0 Hz, 1H), 3.92-4.01 (m, 4H), 3.81 (s, 3H), 3.50(td, J = 7.3, 14.9 Hz, 1H), 1.94 (d, J = 6.5 Hz, 2H), 1.68-1.82 (m, 4H),1.59 (br s, 2H), 1.20-1.29 (m, 1H), 1.09- 1.18 (m, 1H). LCMS m/z = 385[MH]⁺. 133

¹H NMR (DMSO-d₆, 400 MHz): δ 8.69 (s, 1H), 7.98 (dd, J = 2.0, 8.3 Hz,1H), 7.93 (d, J = 2.0 Hz, 1H), 7.23 (s, 1H), 7.07 (d, J = 8.6 Hz, 1H),4.30 (dd, J = 7.5, 8.9 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.95-4.02 (m,3H), 3.88 (s, 2H), 3.83 (s, 3H), 3.54- 3.62 (m, 1H), 1.73-1.81 (m, 2H),1.25- 1.33 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H), 1.12-1.19 (m, 1H), 1.00(t, J = 7.3 Hz, 3H). LCMS m/z = 433 [MH + H₂O]⁺. 134

¹H NMR (CD₃OD, 400 MHz): δ 8.05 (s, 2H), 7.18 (s, 1H), 7.03 (d, J = 8.6Hz, 1H), 4.16-4.22 (m, 1H), 4.07 (t, J = 6.5 Hz, 2H), 3.96-4.02 (m, 1H),3.90 (s, 3H), 3.70 (s, 2H), 3.40-3.46 (m, 1H), 1.81- 1.90 (m, 2H),1.15-1.31 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H). LCMS m/z = 387 [MH]⁺. 135

¹H NMR (DMSO-d₆, 400 MHz): δ 8.61 (s, 1H), 7.68 (dd, J = 8.8, 11.7 Hz,1H), 7.58 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.27 (dd, J = 3.4, 8.3 Hz,1H), 7.08 (d, J = 8.3 Hz, 1H), 4.27 (dd, J = 7.3, 8.8 Hz, 1H), 3.92-4.01(m, 3H), 3.82 (s, 3H), 3.58- 3.65 (m, 1H), 1.71-1.80 (m, 2H), 1.23- 1.31(m, 1H), 1.11-1.19 (m, 1H), 0.99 (t, J = 7.3 Hz, 3H). LCMS m/z = 346[MH]⁺. 136

LCMS m/z = 342.3 [MH]⁺. RT [Analytical SFC Method V] = 6.90 min. 137

LCMS m/z = 342.3 [MH + H₂O]⁺. RT [Analytical SFC Method V] = 7.90 min.138

LCMS m/z = 364.4 [MH]⁺. RT [Prep HPLC Method C] = 2.30 min. 139

¹H NMR (CDCl₃, 400 MHz): δ 8.72-8.92 (m, 1H), 8.50 (br s, 1H), 6.95-7.01(m, 1H), 6.86 (dd, J = 2.3, 8.2 Hz, 1H), 6.51- 6.83 (m, 2H), 4.48 (t, J= 8.2 Hz, 1H), 4.02-4.27 (m, 4H), 3.94 (s, 3H), 3.74 (s, 1H), 1.63 (dt,J = 8.6, 16.6 Hz, 2H), 1.49 (t, J = 7.0 Hz, 2H), 1.23-1.38 (m, 1H). LCMSm/z = 364 [MH]⁺. RT [Analytical SFC Method W] = 3.95 min. 140

¹H NMR (CDCl₃, 400 MHz): δ 8.72-8.92 (m, 1H), 8.50 (br s, 1H), 6.95-7.01(m, 1H), 6.86 (dd, J = 2.3, 8.2 Hz, 1H), 6.51- 6.83 (m, 2H), 4.48 (t, J= 8.2 Hz, 1H), 4.02-4.27 (m, 4H), 3.94 (s, 3H), 3.74 (s, 1H), 1.63 (dt,J = 8.6, 16.6 Hz, 2H), 1.49 (t, J = 7.0 Hz, 2H), 1.23-1.38 (m, 1H). LCMSm/z = 364 [MH]⁺. RT [Analytical SFC Method W] = 3.95 min. 141

¹H NMR (CD₃OD, 400 MHz): δ 8.40 (s, 1H), 8.16 (s, 1H), 6.91 (d, J = 11.0Hz, 1H), 6.82 (d, J = 7.0 Hz, 1H), 4.04 (q, J = 6.9 Hz, 3H), 3.89 (s,4H), 3.64 (br s, 1H), 2.25 (d, J = 1.0 Hz, 3H), 1.39 (t, J = 7.0 Hz,3H), 1.16-1.34 (m, 2H). LCMS m/z = 346 [MH]⁺. 142

¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (s, 1H), 8.48 (s, 1H), 8.22 (s, 1H),7.02 (d, J = 11.5 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 4.26 (t, J = 8.3Hz, 1H), 4.00 (q, J = 7.0 Hz, 2H), 3.93 (br s, 1H), 3.82 (s, 3H),3.64-3.72 (m, 1H), 2.14 (s, 3H), 1.27- 1.38 (m, 4H), 0.98-1.12 (m, 1H).LCMS m/z = 346 [MH]⁺. [α]²⁰ _(D) −8.83 (c = 0.1, EtOH). 143

¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (s, 1H), 8.48 (s, 1H), 8.22 (s, 1H),7.02 (d, J = 11.5 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 4.26 (t, J = 8.3Hz, 1H), 4.00 (q, J = 7.0 Hz, 2H), 3.93 (br s, 1H), 3.82 (s, 3H),3.64-3.72 (m, 1H), 2.14 (s, 3H), 1.27- 1.38 (m, 4H), 0.98-1.12 (m, 1H).LCMS m/z = 346.2 [MH]⁺. RT [Analytical SFC Method X] = 3.52 min. 144

¹H NMR (DMSO-d₆, 400 MHz): δ 8.66 (s, 1H), 7.54 (s, 1H), 7.49 (d, J =7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.26 (br s, 1H), 7.18-7.25 (m,2H), 7.18 (s, 1H), 4.26 (t ,J = 8.2 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H),3.81 (t, J = 8.9 Hz, 1H), 3.43-3.52 (m, 1H), 2.40 (s, 3H), 1.36 (t, J =7.0 Hz, 2H), 1.29 (dd, J = 8.2, 16.3 Hz, 1H), 1.09 (dd, J = 10.1, 16.3Hz, 1H). LCMS m/z = 329 [MH]⁺. 145

¹H NMR (DMSO-d₆, 400 MHz): δ 8.67- 8.79 (m, 2H), 8.48 (d, J = 2.0 Hz,1H), 7.99 (s, 1H), 7.37-7.46 (m, 1H), 7.24- 7.33 (m, 2H), 6.98 (d, J =6.5 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 4.02 (t, J = 6.5 Hz, 2H), 3.87(t, J = 9.0 Hz, 1H), 3.45- 3.60 (m, 1H), 1.69-1.86 (m, 2H), 1.25- 1.38(m, 1H), 1.16 (dd, J = 10.5, 16.1 Hz, 1H), 1.01 (t, J = 7.5 Hz, 3H).LCMS m/z = 298 [MH]⁺. 146

¹H NMR (DMSO-d₆, 400 MHz): δ 8.67- 8.79 (m, 2H), 8.48 (d, J = 2.0 Hz,1H), 7.99 (s, 1H), 7.37-7.46 (m, 1H), 7.24- 7.33 (m, 2H), 6.98 (d, J =6.5 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 4.02 (t, J = 6.5 Hz, 2H), 3.87(t, J = 9.0 Hz, 1H), 3.45- 3.60 (m, 1H), 1.69-1.86 (m, 2H), 1.25- 1.38(m, 1H), 1.16 (dd, J = 10.5, 16.1 Hz, 1H), 1.01 (t, J = 7.5 Hz, 3H).LCMS m/z = 298 [MH]⁺ . [α]²⁰ _(D) −25.7 (c = 0.1, EtOH). 147

¹H NMR (DMSO-d₆, 400 MHz): δ 8.70 (br s, 1H), 7.56-7.64 (m, 1H), 7.47(d, J = 2.2 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 4.29- 4.35 (m, 1H), 4.12(dd, J = 6.7, 9.2 Hz, 1H), 4.01 (t, J = 6.5 Hz, 2H), 3.85 (s, 3H), 3.81(t, J = 7.7 Hz, 1H), 1.72-1.81 (m, 2H), 1.27-1.40 (m, 2H), 1.00 (t, J =7.5 Hz, 3H). LCMS m/z = 335 [MH]⁺. 148

¹H NMR (DMSO-d₆, 400 MHz): δ 8.70 (br s, 1H), 7.56-7.64 (m, 1H), 7.47(d, J = 2.2 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 4.29- 4.35 (m, 1H), 4.12(dd, J = 6.7, 9.2 Hz, 1H), 4.01 (t, J = 6.5 Hz, 2H), 3.85 (s, 3H), 3.81(t, J = 7.7 Hz, 1H), 1.72-1.81 (m, 2H), 1.27-1.40 (m, 2H), 1.00 (t, J =7.5 Hz, 3H). LCMS m/z = 335 [MH]⁺. [α]²⁰ _(D) −10.3 (c = 0.1, EtOH). 149

¹H NMR (DMSO-d₆, 400 MHz): δ 8.65- 8.74 (m, 2H), 8.43 (d, J = 1.7 Hz,1H), 7.91 (t, J = 2.0 Hz, 1H), 7.17-7.30 (m, 2H), 7.05 (d, J = 8.8 Hz,1H), 4.96 (t, J = 5.7 Hz, 1H), 4.27 (t, J = 8.3 Hz, 1H), 3.86 (t, J =9.0 Hz, 1H), 3.79 (s, 3H), 3.41- 3.59 (m, 1H), 1.90 (d, J = 6.4 Hz, 2H),1.66-1.80 (m, 4H), 1.58 (br s, 2H), 1.29 (d, J = 8.3 Hz, 1H), 1.14 (dd,J = 10.4, 16.3 Hz, 1H). LCMS m/z = 354 [MH]⁺. 150

¹H NMR (DMSO-d₆, 400 MHz): δ 8.66 (s, 1H), 7.33-7.44 (m, 3H), 7.26 (d, J= 6.4 Hz, 1H), 6.94-7.05 (m, 2H), 4.23-4.28 (m, 1H), 3.74-3.85 (m, 6H),3.45-3.50 (m, 1H), 1.29 (dd, J = 16.0, 8.0 Hz, 1H), 1.05 (dd, J = 16.0,10.0 Hz, 1H), 1.02-1.09 (m, 1H). LCMS m/z = 317 [MH]⁺. 151

¹H NMR (DMSO-d₆, 400 MHz): δ 8.58 (s, 1H), 7.85 (t, J = 7.7 Hz, 1H),7.60 (d, J = 7.6 Hz, 1H), 7.53-7.58 (m, 1H), 7.43-7.50 (m, 1H), 7.33 (d,J = 7.8 Hz, 1H), 4.25- 4.31 (m, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.09 (t,J = 8.7 Hz, 1H), 3.91 (s, 3H), 3.60-3.68 (m, 1H), 1.21-1.38 (m, 5H).LCMS m/z = 339 [MH]⁺. 152

¹H NMR (DMSO-d₆, 400 MHz): δ 8.66 (s, 1H), 7.91 (s, 1H), 7.85 (d, J =8.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.38-7.33 (m, 2H), 7.24 (d, J =7.6 Hz, 1H), 4.27 (t, J = 8.0 Hz, 1H), 3.97 (s, 3H), 3.80-3.82 (m, 4H),3.43-3.52 (m, 1H), 1.27-1.33 (m, 1H), 1.04-1.10 (m, 1H). LCMS m/z = 300[MH]⁺. 153

¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (s, 1H), 8.57 (d, J = 2.0 Hz, 1H),8.55 (d, J = 1.7 Hz, 1H), 7.93 (s, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.38(d, J = 8.6 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 3.95 (s, 3H), 3.92 (s,3H), 3.84 (t, J = 9.0 Hz, 1H), 3.49-3.57 (m, 1H), 1.32 (dd, J = 8.2,16.3 Hz, 1H), 1.12 (dd, J = 10.4, 16.3 Hz, 1H). LCMS m/z = 325 [MH]⁺.154

¹H NMR (DMSO-d₆, 400 MHz): δ 8.66 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H),7.34 (s, 1H), 6.95 (d, J = 12.7 Hz, 1H), 5.62 (t, J = 5.6 Hz, 1H), 4.57(d, J = 5.9 Hz, 2H), 4.26-4.33 (m, 1H), 4.00 (dd, J = 7.1, 9.0 Hz, 1H),3.93 (t, J = 6.6 Hz, 2H), 3.84 (s, 3H), 3.58-3.66 (m, 1H), 1.69-1.78 (m,2H), 1.25-1.34 (m, 1H), 1.12-1.21 (m, 1H), 0.98 (t, J = 7.3 Hz, 3H).LCMS m/z = 377 [MH]⁺. [α]²⁰ _(D) −11.9 (c = 0.1, EtOH). 155

¹H NMR (DMSO-d₆, 400 MHz): δ 8.68 (s, 1H), 8.13 (s, 1H), 8.01 (d, J =7.2 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.48(t, J = 7.6 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 6.26 (s, 1H), 4.97 (s,2H), 4.37 (t, J = 6.8 Hz, 2H), 3.83 (s, 3H), 1.80 (q, J = 6.8 Hz, 2H),1.00 (t, J = 6.8 Hz, 3H). LCMS m/z = 326 [MH]⁺. 156

¹H NMR (DMSO-d₆, 400 MHz): δ 8.68 (s, 1H), 8.13 (s, 1H), 8.01 (d, J =7.2 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.48(t, J = 7.6 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 6.26 (s, 1H), 4.97 (s,2H), 4.37 (t, J = 6.8 Hz, 2H), 3.83 (s, 3H), 1.80 (q, J = 6.8 Hz, 2H),1.00 (t, J = 6.8 Hz, 3H). LCMS m/z = 328 [MH]⁺. 157

¹H NMR (DMSO-d₆, 400 MHz): δ 8.65 (s, 1H), 7.12-7.22 (m, 2H), 7.09 (s,1H), 6.95-7.05 (m, 3H), 6.79 (s, 1H), 4.24 (t, J = 8.2 Hz, 1H), 3.84 (s,3H), 3.79 (d, J = 8.0 Hz, 7H), 3.40-3.50 (m, 1H), 1.19-1.33 (m, 1H),1.08 (dd, J = 10.0, 16.1 Hz, 1H), 1.01-1.13 (m, 1H). LCMS m/z = 329[MH]⁺. 158

¹H NMR (DMSO-d₆, 400 MHz): δ 8.58 (br s, 1H), 7.69 (d, J = 1.5 Hz, 1H),7.63 (d, J = 8.3 Hz, 1H), 7.59 (s, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.99(s, 1H), 4.26 (t, J = 8.1 Hz, 1H), 4.00 (t, J = 6.6 Hz, 2H), 3.96 (dd, J= 6.8, 8.8 Hz, 1H), 3.80 (s, 3H), 3.49-3.57 (m, 1H), 2.34 (s, 3H), 1.72-1.80 (m, 2H), 1.20-1.28 (m, 1H), 1.13- 1.20 (m, 1H), 1.00 (t, J = 7.3Hz, 3H). LCMS m/z = 342 [MH]⁺. 159

¹H NMR (DMSO-d₆, 400 MHz): δ 8.64 (s, 1H), 7.42-7.48 (m, 2H), 7.31 (s,1H), 7.05 (d, J = 8.1 Hz, 1H), 4.26 (dd, J = 7.7, 8.7 Hz, 1H), 3.93 (dd,J = 7.6, 8.8 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.56-3.62 (m, 1H),1.24-1.34 (m, 1H), 1.12-1.20 (m, 1H). LCMS m/z = 306 [MH]⁺. 160

LCMS m/z = 319.9 [MH]⁺. RT [Analytical SFC Method Y] = 5.76 min. 161

¹H NMR (DMSO-d₆, 400 MHz): δ 7.98 (s, 1H), 7.55-7.57 (m, 1H), 7.50-7.52(m, 2H), 7.39-7.41 (m, 1H), 7.28-7.37 (m, 1H), 4.26 (t, J = 8.0 Hz, 1H),3.89 (s, 3H), 3.88 (s, 3H), 3.82 (t, J = 8.0 Hz, 1H), 3.32-3.79 (m, 1H),1.28-1.32 (m, 1H), 1.03-1.14 (m, 1H). LCMS m/z = 300 [MH]⁺. 162

¹H NMR (DMSO-d₆, 400 MHz): δ 8.59 (s, 1H), 7.78 (t, J = 8.0 Hz, 1H),7.67 (t, J = 8.8 Hz, 1H), 7.54-7.57 (m, 1H), 7.25 (d, J = 8.0 Hz, 1H),7.02 (d, J = 9.2 Hz, 1H), 4.26-4.30 (m, 1H), 4.01-4.97 (m, 1H), 3.88 (s,3H), 3.82 (s, 3H), 3.32-3.65 (m, 1H), 1.18-1.30 (m, 2H). LCMS m/z = 318[MH]⁺. 163

¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H),8.46 (s, 1H), 7.78 (s, 1H), 7.06 (d, J = 12.2 Hz, 1H), 4.28 (t, J = 8.3Hz, 1H), 4.02 (q, J = 7.3 Hz, 2H), 3.88 (s, 3H), 3.81 (t, J = 8.8 Hz,1H), 3.47-3.55 (m, 1H), 1.22-1.38 (m, 4H), 1.00-1.13 (m, 1H). LCMS m/z =350 [MH]⁺. 164

¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H),8.46 (s, 1H), 7.78 (s, 1H), 7.06 (d, J = 12.2 Hz, 1H), 4.28 (t, J = 8.3Hz, 1H), 4.02 (q, J = 7.3 Hz, 2H), 3.88 (s, 3H), 3.81 (t, J = 8.8 Hz,1H), 3.47-3.55 (m, 1H), 1.22-1.38 (m, 4H), 1.00-1.13 (m, 1H). LCMS m/z =318 [MH]⁺. [α]²⁰ _(D) −20.6 (c = 0.22, EtOH). 165

166

¹H NMR (DMSO-d₆, 400 MHz): δ 7.36- 7.39 (m, 2H), 7.31-7.32 (m, 1H), 7.27(d, J = 7.6 Hz, 1H), 7.15-7.19 (m, 1H), 6.96 (d, J = 8.8 Hz, 1H), 4.25(t, J = 8.0 Hz, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.79 (t, J= 8.8 Hz, 1H), 3.41-3.50 (m, 1H), 1.26-1.32 (m, 4H), 1.02-108 (m, 1H).LCMS m/z = 331 [MH]⁺. 167

¹H NMR (DMSO-d₆, 400 MHz): δ 8.70 (s, 1H), 8.47 (d, J = 2.0 Hz, 1H),8.42 (d, J = 2.0 Hz, 1H), 7.73 (t, J = 2.1 Hz, 1H), 7.09 (d, J = 8.8 Hz,1H), 6.91 (d, J = 8.6 Hz, 1H), 4.25-4.32 (m, 1H), 3.90 (t, J = 6.5 Hz,2H), 3.79-3.87 (m, 4H), 3.65 (s, 3H), 3.45-3.54 (m, 1H), 1.65-1.76 (m,2H), 1.32 (dd, J = 8.2, 16.3 Hz, 1H), 1.03-1.12 (m, 1H), 0.99 (t, J =7.5 Hz, 3H). LCMS m/z = 358 [MH]⁺. 168

¹H NMR (DMSO-d₆, 400 MHz): δ 8.70 (s, 1H), 8.47 (d, J = 2.0 Hz, 1H),8.42 (d, J = 2.0 Hz, 1H), 7.73 (t, J = 2.1 Hz, 1H), 7.09 (d, J = 8.8 Hz,1H), 6.91 (d, J = 8.6 Hz, 1H), 4.25-4.32 (m, 1H), 3.90 (t, J = 6.5 Hz,2H), 3.79-3.87 (m, 4H), 3.65 (s, 3H), 3.45-3.54 (m, 1H), 1.65-1.76 (m,2H), 1.32 (dd, J = 8.2, 16.3 Hz, 1H), 1.03-1.12 (m, 1H), 0.99 (t, J =7.5 Hz, 3H). LCMS m/z = 358 [MH]⁺. [α]²⁰ _(D) −18.8 (c = 0.1, EtOH). 169

¹H NMR (DMSO-d₆, 400 MHz): δ 8.69 (br s, 1H), 8.42 (br s, 1H), 7.90 (brs, 1H), 7.34 (s, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 8.3 Hz,1H), 4.44-4.54 (m, 1H), 4.27 (t, J = 7.8 Hz, 1H), 3.74-3.89 (m, 4H),3.45-3.56 (m, 1H), 2.75-2.85 (m, 2H), 2.56-2.66 (m, 2H), 2.13-2.18 (m,2H), 1.76-1.88 (m, 2H), 1.27-1.37 (m, 1H), 1.14 (dd, J = 10.3, 16.1 Hz,1H). LCMS m/z = 386 [MH]⁺. 170

¹H NMR (DMSO-d₆, 400 MHz): δ 8.69 (br s, 1H), 8.42 (br s, 1H), 7.90 (brs, 1H), 7.34 (s, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 8.3 Hz,1H), 4.44-4.54 (m, 1H), 4.27 (t, J = 7.8 Hz, 1H), 3.74-3.89 (m, 4H),3.45-3.56 (m, 1H), 2.75-2.85 (m, 2H), 2.56-2.66 (m, 2H), 2.13-2.18 (m,2H), 1.76-1.88 (m, 2H), 1.27-1.37 (m, 1H), 1.14 (dd, J = 10.3, 16.1 Hz,1H). LCMS m/z = 386 [MH]⁺. RT [Analytical SFC Method Z] = 5.20 min. 171

¹H NMR (DMSO-d₆, 400 MHz): δ 8.65 (s, 1H), 8.39 (s, 1H), 7.43 (s, 1H),7.02 (d, J = 8.0 Hz, 1H), 6.90 (s, 1H), 6.84 (d, J = 8.3 Hz, 1H), 4.24(t, J = 8.3 Hz, 1H), 4.03 (q, J = 6.8 Hz, 2H), 3.75-3.84 (m, 4H),3.39-3.52 (m, 1H), 2.69 (q, J = 7.4 Hz, 2H), 1.21-1.37 (m, 4H),1.00-1.17 (m, 4H). LCMS m/z = 342 [MH]⁺. 172

¹H NMR (DMSO-d₆, 400 MHz): δ 8.66 (s, 1H), 7.54 (s, 1H), 7.49 (d, J =7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 9.8 Hz, 2H),7.17-7.22 (m, 2H), 4.26 (t, J = 8.2 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H),3.81 (t, J = 8.9 Hz, 1H), 3.43-3.52 (m, 1H), 2.40 (s, 3H), 1.36 (t, J =7.0 Hz, 3H), 1.29 (dd, J = 8.2, 16.3 Hz, 1H), 1.09 (dd, J = 10.1, 16.3Hz, 1H). LCMS m/z = 329 [MH]⁺. 173

¹H NMR (DMSO-d₆, 400 MHz): δ 8.75 (d, J = 2.0 Hz, 1H), 8.70 (s, 1H),8.48 (d, J = 2.0 Hz, 1H), 8.02 (t, J = 2.2 Hz, 1H), 7.42 (d, J = 2.0 Hz,1H), 7.34 (d, J = 2.0 Hz, 1H), 4.18-4.30 (m, 3H), 3.83-3.91 (m, 1H),3.81 (s, 3H), 3.44-3.57 (m, 1H), 1.39 (t, J = 6.9 Hz, 3H), 1.26-1.34 (m,1H), 1.12-1.22 (m, 1H). LCMS m/z = 348 [MH]⁺. RT [Analytical SFC MethodE] = 5.33 min 174

¹H NMR (DMSO-d₆, 400 MHz): δ 8.65 (s, 1H), 8.24 (s, 1H), 7.94 (s, 1H),7.87 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.29(d, J = 7.2 Hz, 1H), 4.27 (t, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.89 (s,3H), 3.82 (t, J = 8.4 Hz, 1H), 3.44-3.53 (m, 1H), 1.30 (q, J = 8.0 Hz,1H), 1.08 (q, J = 10.0 Hz, 1H). LCMS m/z = 300 [MH]⁺. 175

¹H NMR (DMSO-d₆, 400 MHz): δ 8.60 (s, 1H), 7.72-7.79 (m, 2H), 7.23 (s,1H), 7.05 (d, J = 8.5 Hz, 1H), 4.92 (br s, 1H), 4.29 (t, J = 8.0 Hz,1H), 4.10 (dd, J = 6.0, 8.5 Hz, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 3.55-3.63 (m, 14.2 Hz, 1H), 1.93 (d, J = 5.5 Hz, 2H), 1.72 (br s, 4H), 1.58(br s, 2H), 1.22-1.36 (m, 2H). LCMS m/z = 385 [MH]⁺. 176

¹H NMR (DMSO-d₆, 400 MHz): δ 8.60 (s, 1H), 7.72-7.79 (m, 2H), 7.23 (s,1H), 7.05 (d, J = 8.5 Hz, 1H), 4.92 (br s, 1H), 4.29 (t, J = 8.0 Hz,1H), 4.10 (dd, J = 6.0, 8.5 Hz, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 3.55-3.63 (m, 14.2 Hz, 1H), 1.93 (d, J = 5.5 Hz, 2H), 1.72 (br s, 4H), 1.58(br s, 2H), 1.22-1.36 (m, 2H). LCMS m/z = 385 [MH]⁺. RT [Analytical SFCMethod Z] = 2.79 min. 177

¹H NMR (DMSO-d₆, 400 MHz): δ 7.19- 7.53 (m, 7H) 4.22-4.31 (m, 1H), 3.94(s, 3H), 3.91 (s, 3H), 3.79-3.83 (t, J = 8.8 Hz, 1H), 3.42-3.53 (m, 1H),1.26-1.32 (m, 1H), 1.04-1.11 (m, 1H). LCMS m/z = 322 [MH]⁺. 178

¹H NMR (DMSO-d₆, 400 MHz): δ 8.89 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.0Hz, 1H), 8.24 (s, 1H), 8.20 (s, 1H), 7.47 (s, 1H), 4.18 (t, J = 6.4 Hz,2H), 3.97 (s, 3H), 3.87 (br s, 1H), 3.39 (br s, 1H), 1.85-1.94 (m, 2H),1.29 (d, J = 8.8 Hz, 2H), 1.10 (t, J = 7.6 Hz, 3H). LCMS m/z = 329[MH]⁺. 179

¹H NMR (DMSO-d₆, 400 MHz): δ 8.89 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.0Hz, 1H), 8.24 (s, 1H), 8.20 (s, 1H), 7.47 (s, 1H), 4.18 (t, J = 6.4 Hz,2H), 3.97 (s, 3H), 3.87 (br s, 1H), 3.39 (br s, 1H), 1.85-1.94 (m, 2H),1.29 (d, J = 8.8 Hz, 2H), 1.10 (t, J = 7.6 Hz, 3H). LCMS m/z = 329[MH]⁺. RT [Analytical SFC Method G] = 4.36 min. 180

¹H NMR (DMSO-d₆, 400 MHz): δ 8.73 (s, 1H), 7.61-7.67 (m, 3H), 7.26 (s,1H), 7.03 (d, J = 8.3 Hz, 1H), 5.40 (t, J = 5.9 Hz, 1H), 4.58 (d, J =5.4 Hz, 2H), 4.29 (t, J = 8.3 Hz, 1H), 4.00 (t, J = 6.6 Hz, 2H), 3.85(t, J = 8.8 Hz, 1H), 3.81 (s, 3H), 3.46- 3.54 (m, 1H), 1.72-1.81 (m,2H), 1.32 (dd, J = 8.3, 16.1 Hz, 1H), 1.09 (dd, J = 9.5, 16.4 Hz, 1H),0.98-1.03 (m, 3H). LCMS m/z = 358 [MH]⁺. RT [Analytical SFC Method L] =3.58 min. 181

¹H NMR (DMSO-d₆, 400 MHz): δ 8.69 (s, 1H), 7.78 (d, J = 2.2 Hz, 1H),7.60 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 4.32 (dd, J = 7.6,9.0 Hz, 1H), 4.12 (dd, J = 6.6, 9.0 Hz, 1H), 3.97-3.99 (m, 1H),3.76-3.88 (m, 4H), 1.25-1.43 (m, 2H), 0.77-0.86 (m, 2H), 0.67-0.74 (m,2H). LCMS m/z = 333 [MH]⁺. [α]²⁰ _(D) −12.7 (c = 0.1, EtOH). 182

¹H NMR (DMSO-d₆, 400 MHz): δ 7.50 (br s, 1H), 7.46 (d, J = 7.8 Hz, 1H),7.35 (t, J = 7.8 Hz, 1H), 7.14-7.22 (m, 3H), 7.01 (d, J = 8.2 Hz, 1H),4.26 (t, J = 7.8 Hz, 1H), 4.04 (q, J = 7.0 Hz, 2H), 3.79-3.84 (m, 4H),3.42-3.51 (m, 1H), 1.26-1.36 (m, 4H), 1.05-1.12 (m, 1H). LCMS m/z = 313[MH]⁺. 183

¹H NMR (DMSO-d₆, 400 MHz): δ 7.44- 7.56 (m, 2H), 7.32-7.39 (m, 1H),7.15- 7.24 (m, 3H), 7.00-7.04 (m, 1H), 4.15 (t, J = 10.5 Hz, 1H),4.02-4.06 (m, 1H), 3.79-3.84 (m, 5H), 3.43-3.51 (m, 1H), 1.99-2.09 (m,1H), 1.22-1.32 (m, 1H), 1.05-1.11 (m, 1H), 0.98-1.01 (m, 6H). LCMS m/z =359 [MH + H₂O]⁺. 184

¹H NMR (DMSO-d₆, 400 MHz): δ 7.46 (s, 1H), 7.40-7.44 (m, 1H), 7.36 (d, J= 7.6 Hz, 1H), 7.21 (d, J = 7.3 Hz, 1H), 7.16 (dd, J = 2.1, 8.4 Hz, 1H),6.99-7.05 (m, 2H), 4.75-4.83 (m, 1H), 4.26 (t, J = 8.2 Hz, 1H),3.78-3.84 (m, 4H), 3.41-3.54 (m, 1H), 2.39-2.47 (m, 2H), 2.02-2.14 (m,2H), 1.74-1.84 (m, 1H), 1.59-1.71 (m, 1H), 1.29 (dd, J = 8.2, 16.3 Hz,1H), 1.05-1.12 (m, 1H), 1.03 (d, J = 6.8 Hz, 1H). LCMS m/z = 339 [MH]⁺.185

¹H NMR (DMOS-d₆, 400 MHz): δ 8.67 (s, 1H), 7.99 (dd, J = 2.0, 8.5 Hz,1H), 7.96 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.64 (s, 1H),4.26 (dd, J = 7.3, 8.8 Hz, 1H), 4.10 (q, J = 6.9 Hz, 2H), 4.00 (s, 3H),3.95 (dd, J = 6.0, 9.0 Hz, 1H), 3.83 (s, 3H), 3.48-3.54 (m, 1H), 1.37(t, J = 7.0 Hz, 3H). 1.21-1.27 (m, 1H), 1.11-1.18 (m, 1H). LCMS m/z =345 [MH]⁺. 186

¹H NMR (DMSO-d₆, 400 MHz): δ 8.67 (s, 1H), 7.99 (dd, J = 2.0, 8.5 Hz,1H), 7.96 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.64 (s, 1H),4.26 (dd, J = 7.3, 8.8 Hz, 1H), 4.10 (q, J = 6.9 Hz, 2H), 4.00 (s, 3H),3.95 (dd, J = 6.0, 9.0 Hz, 1H), 3.83 (s, 3H), 3.48-3.54 (m, 1H), 1.37(t, J = 7.0 Hz, 3H), 1.21-1.27 (m, 1H), 1.11-1.18 (m, 1H). LCMS m/z =345 [MH]⁺. [α]²⁰ _(D) −37.4 (c = 0.1, EtOH). 187

¹H NMR (DMSO-d₆, 400 MHz): δ 8.73 (s, 1H), 8.71 (d, J = 2.0 Hz, 1H),8.42 (d, J = 2.0 Hz, 1H), 7.94 (t, J = 2.2 Hz, 1H), 7.28 (d, J = 2.0 Hz,1H), 7.21-7.25 (m, 1H), 7.03-7.07 (m, 1H), 4.27 (t, J = 8.3 Hz, 1H),4.05 (q, J = 7.2 Hz, 2H), 3.83-3.88 (m, 4H), 3.47-3.55 (m, 1H),1.27-1.37 (m, 4H), 1.10-1.19 (m, 1H). LCMS m/z = 314 [MH]⁺. 188

¹H NMR (DMSO-d₆, 400 MHz): δ 8.73 (s, 1H), 8.71 (d, J = 2.0 Hz, 1H),8.42 (d, J = 2.0 Hz, 1H), 7.94 (t, J = 2.2 Hz, 1H), 7.28 (d, J = 2.0 Hz,1H), 7.21-7.25 (m, 1H), 7.03-7.07 (m, 1H), 4.27 (t, J = 8.3 Hz, 1H),4.05 (q, J = 7.2 Hz, 2H), 3.83-3.88 (m, 4H), 3.47-3.55 (m, 1H),1.27-1.37 (m, 4H), 1.10-1.19 (m, 1H). LCMS m/z = 314 [MH]⁺. RT[Analytical SFC Method AA] = 3.61 min. 189

¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H),7.04 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H), 6.82-6.85 (m, 1H),4.24-4.28 (m, 1H), 4.03 (q, J = 7.0 Hz, 2H), 3.90-3.95 (m, 1H), 3.80 (s,3H), 3.63-3.71 (m, 1H), 2.22 (s, 3H), 1.30-1.36 (m, 4H), 1.04-1.10 (m,1H). LCMS m/z = 328 [MH]⁺. RT [Analytical SFC Method E] = 5.71 min. 190

¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (s, 1H), 8.69 (d, J = 2.0 Hz, 1H),8.42 (d, J = 2.0 Hz, 1H), 7.92 (t, J = 2.0 Hz, 1H), 7.29- 7.24 (m, 2H),7.07 (d, J = 8.0 Hz, 1H), 4.68 -4.74 (m, 1H), 4.27 (t, J = 8.3 Hz, 1H),3.86 (t, J = 9.0 Hz, 1H), 3.79 (s, 3H), 3.47-3.55 (m, 1H), 1.26-1.35 (m,7H), 1.10-1.18 (m, 1H). LCMS m/z = 328 [MH]⁺. RT [Analytical SFC MethodBA] = 5.69 min. 191

¹H NMR (DMSO-d₆, 400 MHz): δ 7.31- 7.46 (m, 3H), 7.33-7.36 (m, 2H), 7.27(d, J = 8.8 Hz, 1H), 4.18-4.28 (m, 3H), 3.90 (s, 3H), 3.81 (t, J = 8.8Hz, 1H), 3.45- 3.52 (m, 1H), 1.26-1.34 (m, 4H), 1.08- 1.11 (m, 1H). LCMSm/z = 338 [MH]⁺. 192

RT [Analytical SFC Method CA] = 3.14 min. 193

¹H NMR (DMSO-d₆, 400 MHz): δ 8.69- 8.72 (m, 2H), 8.44 (d, J = 2.0 Hz,1H), 7.91 (t, J = 2.0 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.28 (dd, J =2.4, 8.3 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 4.25-4.31 (m, 1H), 3.97-4.01(m, 1H), 3.86 (t, J = 88 Hz, 1H), 3.78 (s, 3H), 3.46-3.57 (m, 1H), 1.32(dd, J = 8.1, 16.4 Hz, 1H), 1.14 (dd, J = 10.3, 16.1 Hz, 1H), 0.76-0.83(m, 2H), 0.67-0.72 (m, 2H). LCMS m/z = 326 [MH]⁺. RT [Analytical SFCMethod D] = 5.38 min. 194

¹H NMR (DMSO-d₆, 400 MHz): δ 8.66 (br s, 1H), 7.42-7.46 (m, 2H), 7.30(s, 1H), 7.05 (d, J = 8.3 Hz, 1H), 4.24-4.28 (m, 1H), 4.09 (q, J = 7.0Hz, 2H), 3.90-3.95 (m, 1H), 3.82 (s, 3H), 3.55-3.63 (m, 1H), 1.36 (t, J= 7.0 Hz, 3H), 1.25-1.31 (m, 1H), 1.11-1.18 (m, 1H). LCMS m/z = 320[MH]⁺. RT [Analytical SFC Method DA] = 4.47 min. [α]²⁰ _(D) −17.4 (c =0.1, EtOH). 195

¹H NMR (DMSO-d₆, 400 MHz): δ 8.65 (s, 1H), 7.97 (dd, J = 2.0, 8.3 Hz,1H), 7.93 (d, J = 1.7 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 6.64 (s, 1H),4.89 (t, J = 5.4 Hz, 1H), 4.42-4.47 (m, 2H), 4.26 (dd, J = 7.3, 9.0 Hz,1H), 4.00 (t, J = 6.5 Hz, 2H), 3.95 (dd, J = 6.4, 9.0 Hz, 1H), 3.83 (s,3H), 3.74-3.80 (m, 2H), 3.47-3.54 (m, 1H), 1.73-1.81 (m, 2H), 1.20-1.28(m, 1H), 1.10-1.17 (m, 1H), 1.01 (t, J = 7.3 Hz, 3H). LCMS m/z = 406[MH + H₂O)⁺. 196

¹H NMR (DMSO-d₆, 400 MHz): δ 8.65 (s, 1H), 7.97 (dd, J = 2.0, 8.3 Hz,1H), 7.93 (d, J = 1.7 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 6.64 (s, 1H),4.89 (t, J = 5.4 Hz, 1H), 4.42-4.47 (m, 2H), 4.26 (dd, J = 7.3, 9.0 Hz,1H), 4.00 (t, J = 6.5 Hz, 2H), 3.95 (dd, J = 6., 9.0 Hz, 1H), 3.83 (s,3H), 3.74-3.80 (m, 2H), 3.47-3.54 (m, 1H), 1.73-1.81 (m, 2H), 1.20-1.28(m, 1H), 1.10-1.17 (m, 1H), 1.01 (t, J = 7.3 Hz, 3H). LCMS m/z = 406[MH + H₂O]⁺. [α]²⁰ _(D) −38.9 (c = 0.1, EtOH). 197

¹H NMR (DMSO-d₆, 400 MHz): δ 8.59 (s, 1H), 7.73-7.75 (m, 3H), 7.64 (d, J= 8.4 Hz, 1H), 7.15-7.17 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.27-4.31(m, 1H), 3.95-3.99 (m, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.57- 3.60 (m,1H), 1.15-1.29 (m, 2H). LCMS m/z = 298 [MH]⁻. 198

¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (br s, 1H), 7.70-7.81 (m, 3H), 7.53(d, J = 8.0 Hz, 1H), 7.07-7.14 (m, 1H), 5.71 (br s, 1H), 4.55 (d, J =5.5 Hz, 2H), 4.29 (t, J = 8.3 Hz, 1H), 3.95-4.11 (m, 2H), 3.81-3.88 (m,4H), 1.71-1.83 (m, 2H), 1.27 (d, J = 8.0 Hz, 1H), 0.96-1.05 (m, 4H).LCMS m/z = 359 [MH]⁺. 199

¹H NMR (DMSO-d₆, 400 MHz): δ 8.60 (br s, 1H), 7.75-7.82 (m, 1H), 7.67(t, J = 8.8 Hz, 1H), 7.55 (d, J = 6.4 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H),7.02 (d, J = 8.1 Hz, 1H), 4.25-4.32 (m, 1H), 4.06 (q, J = 7.0 Hz, 2H),3.96-4.02 (m, 1H), 3.87 (s, 3H), 3.61 (td, J = 8.0, 15.8 Hz, 1H),1.13-1.32 (m, 5H). LCMS m/z = 332 [MH]⁺. 200

¹H NMR (DMSO-d₆, 400 MHz): δ 8.61 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H),7.33 (d, J = 2.5 Hz, 1H), 7.25 (dd, J = 2.5, 8.5 Hz, 1H), 7.01 (d, J =9.0 Hz, 1H), 6.37 (d, J = 2.5 Hz, 1H), 4.18-4.25 (m, 1H), 3.98 (t, J =6.5 Hz, 2H), 3.89 (t, J = 8.5 Hz, 1H), 3.78 (s, 3H), 3.44-3.52 (m, 1H),1.71- 1.80 (m, 2H), 1.27 (dd, J = 8.5, 16.1 Hz, 1H), 1.03-1.13 (m, 1H),0.99 (t, J = 7.3 Hz, 3H). LCMS m/z = 317 [MH]⁺. 201

¹H NMR (DMSO-d₆, 400 MHz): δ 8.60 (br s, 1H), 7.75-7.82 (m, 1H), 7.67(t, J = 8.8 Hz, 1H), 7.55 (d, J = 6.4 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H),7.02 (d, J = 8.1 Hz, 1H), 4.25-4.32 (m, 1H), 4.06 (q, J = 7.0 Hz, 2H),3.96-4.02 (m, 1H), 3.87 (s, 2H), 3.57-3.65 (m, 1H), 1.13-1.33 (m, 5H).LCMS m/z = 316 [MH]⁺. 202

¹H NMR (DMSO-d₆, 400 MHz): δ 8.74 (s, 1H), 7.61-7.69 (m, 3H), 7.26 (s,1H), 7.03 (d, J = 8.3 Hz, 1H), 5.40 (t, J = 5.6 Hz, 1H), 4.58 (d, J =5.9 Hz, 2H), 4.29 (t, J = 8.3 Hz, 1H), 4.00 (t, J = 6.4 Hz, 2H),3.82-3.89 (m, 1H), 3.81 (s, 3H), 3.47- 3.56 (m, 1H), 1.72-1.81 (m, 2H),1.32 (dd, J = 8.3, 16.1 Hz, 1H), 1.09 (dd, J = 9.8, 16.6 Hz, 1H), 1.01(t, J = 7.6 Hz, 3H). LCMS m/z = 358 [MH]⁺. 203

¹H NMR (DMSO-d₆, 400 MHz): δ 8.61 (br s, 1H), 7.44-7.83 (m, 2H),7.67-7.73 (m, 2H), 7.18-7.24 (m, 2H), 4.26-4.32 (m, 1H), 4.19 (q, J =7.1 Hz, 2H), 3.97 (dd, J = 6.6, 8.8 Hz, 1H), 3.57-3.64 (m, 1H), 2.42 (s,3H), 1.38 (t, J = 7.0 Hz, 3H), 1.22-1.31 (m, 1H), 1.14-1.22 (m, 1H).LCMS m/z = 330 [MH]⁺. 204

RT [Analytical SFC Method Y] = 7.70 min. 205

¹H NMR (DMSO-d₆, 400 MHz): δ 8.70 (d, J = 2.0 Hz, 1H), 8.31 (s, 1H),7.03 (d, J = 7.8 Hz, 1H), 6.72 (dd, J = 2.0, 3.9 Hz, 1H), 6.65 (ddd, J =2.0, 4.2, 8.1 Hz, 1H), 4.22 (dd, J = 7.3, 8.8 Hz, 1H), 3.96-4.01 (m,2H), 3.84-3.92 (m, 1H), 3.80 (s, 3H), 3.54-3.62 (m, 1H), 2.13 (s, 3H),1.97 (s, 3H), 1.25-1.34 (m, 4H), 0.99-1.09 (m, 1H). LCMS m/z = 342[MH]⁺. [α]²⁰ _(D) +9.6 (c = 0.1, EtOH). 206

¹H NMR (DMSO-d₆, 400 MHz): δ 8.65 (s, 1H), 7.56 (s, 1H), 7.51 (d, J =7.8 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 8.1 Hz, 2H), 7.20(d, J = 8.6 Hz, 2H), 4.26 (t, J = 8.2 Hz, 1H), 3.91 (s, 3H), 3.82 (t, J= 8.9 Hz, 1H), 3.44-3.52 (m, 1H), 2.41 (s, 3H), 1.29 (dd, J = 8.2, 16.3Hz, 1H), 1.09 (dd, J = 10.3, 16.1 Hz, 1H). LCMS m/z = 315 [MH]⁺. 207

¹H NMR (DMSO-d₆, 400 MHz): δ 8.64 (s, 1H), 7.27-7.30 (m, 2H), 7.14-7.18(m, 2H), 6.99-7.02 (m, 2H), 4.22-4.26 (m, 1H), 3.78-3.84 (m, 7H),3.37-3.46 (m, 1H), 2.34 (s, 3H), 1.24-1.30 (m, 1H), 1.04-1.11 (m, 1H).LCMS m/z 313 [MH]⁺. 208

¹H NMR (DMSO-d₆, 400 MHz): δ 8.89 (s, 1H), 8.73 (s, 1H), 8.49 (d, J =2.0 Hz, 1H), 8.09 (s, 1H), 7.49 (d, J = 12.0 Hz, 1H), 4.28-4.33 (m, 3H),3.87 (s, 3H), 3.82 (t, J = 8.7 Hz, 1H), 3.49-3.57 (m, 1H), 1.73-1.81 (m,2H), 1.31-1.37 (m, 1H), 1.03-1.09 (m, 1H), 0.98 (t, J = 7.5 Hz, 3H).LCMS m/z = 347 [MH]⁺. [α]²⁰ _(D) +20.4 (c = 0.1, EtOH). 209

¹H NMR (DMSO-d₆, 400 MHz): δ 8.66 (br s, 1H), 7.35-7.40 (m, 2H),7.26-7.34 (m, 2H), 7.18 (t, J = 8.4 Hz, 1H), 6.95-7.00 (m, 1H),4.22-4.28 (m, 1H), 3.86 (s, 3H), 3.77-3.84 (m, 4H), 3.41-3.52 (m, 1H),1.29 (q, J = 8.0 Hz, 1H), 1.04 (q, 8.0 Hz, 1H). LCMS m/z = 317 [MH]⁺.210

¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (s, 1H), 8.50 (d, J = 5.4 Hz, 1H),7.77 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 2.2, 8.6 Hz, 1H),7.18 (dd, J = 1.2, 5.1 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 4.87- 4.94 (m,1H), 4.24-4.31 (m, 1H), 3.84 (t, J = 9.0 Hz, 1H), 3.79 (s, 3H),3.42-3.55 (m, 1H), 1.87-1.96 (m, 2H), 1.70-1.80 (m, 4H), 1.56-1.63 (m,2H), 1.30 (dd, J = 8.3, 16.1 Hz, 1H), 1.10 (dd, J = 10.0, 16.4 Hz, 1H).LCMS m/z = 354 [MH]⁺. 211

¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (s, 1H), 8.50 (d, J = 5.4 Hz, 1H),7.77 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 2.2, 8.6 Hz, 1H),7.18 (dd, J = 1.2, 5.1 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 4.87- 4.94 (m,1H), 4.24-4.31 (m, 1H), 3.84 (t, J = 9.0 Hz, 1H), 3.79 (s, 3H),3.42-3.55 (m, 1H), 1.87-1.96 (m, 2H), 1.70-1.80 (m, 4H), 1.56-1.63 (m,2H), 1.30 (dd, J = 8.3, 16.1 Hz, 1H), 1.10 (dd, J = 10.0, 16.4 Hz, 1H).LCMS m/z = 354 [MH]⁺. RT [Analytical SFC Method EA] = 4.27 min. 212

¹H NMR (DMSO-d₆, 400 MHz): δ 8.71 (d, J = 5.1 Hz, 1H), 8.69 (s, 1H),8.00 (dd, J = 1.8, 8.4 Hz, 1H), 7.96 (d, J = 1.7 Hz, 1H), 7.26 (d, J =4.9 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 4.30 (dd, J = 7.5, 8.9 Hz, 1H),3.97-4.02 (m, 3H), 3.83 (s, 3H), 3.55-3.63 (m, 1H), 1.73-1.82 (m, 2H),1.25-1.33 (m, 1H), 1.13-1.20 (m, 1H), 1.01 (t, J = 7.5 Hz, 3H). LCMS m/z= 329 [MH]⁺. 213

¹H NMR (DMSO-d₆, 400 MHz): δ 8.61 (s, 1H), 7.75-7.80 (m, 1H), 7.66 (t, J= 8.8 Hz, 1H), 7.55 (dd, J = 1.8, 7.7 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H),6.99-7.04 (m, 1H), 4.27 (dd, J = 7.8, 8.6 Hz, 1H), 3.92- 4.02 (m, 3H),3.86 (s, 3H), 3.57-3.65 (m, 1H), 1.63-1.72 (m, 2H), 1.14-1.31 (m, 2H),0.98 (t, J = 7.3 Hz, 3H). LCMS m/z = 346 [MH]⁺. 214

¹H NMR (DMSO-d₆, 400 MHz): δ 8.75 (d, J = 2.0 Hz, 1H), 8.71 (s, 1H),8.47 (d, J = 1.47 Hz, 1H), 8.00 (s, 1H), 7.27 (dd, J = 2.0, 11.7 Hz,1H), 7.20 (s, 1H), 4.27 (t, J = 8.3 Hz, 1H), 4.21 (q, J = 6.9 Hz, 2H),3.82-3.90 (m, 3H), 3.45-3.56 (m, 2H), 1.39 (t, J = 6.9 Hz, 3H),1.26-1.34 (m, 1H), 1.12-1.20 (m, 1H). LCMS m/z = 349 [MH + H₂O]⁺. RT[Analytical SFC Method D] = 4.59 min. 215

¹H NMR (DMSO-d₆, 400 MHz): δ 8.81 (d, J = 2.4 Hz, 1H), 8.69 (s, 1H),8.53 (s, 1H), 7.67 (t, J = 8.8 Hz, 1H), 707 (d, J = 7.8 Hz, 1H), 4.31(t, J = 8.3 Hz, 1H), 3.94-4.06 (m, 3H), 3.89 (s, 3H), 3.67- 3.75 (m,1H), 1.64-1.73 (m, 2H), 1.27- 1.36 (m, 1H), 1.15-1.25 (m, 1H), 0.98 (t,J = 7.3 Hz, 3H). LCMS m/z = 347 [MH]⁺. 216

¹H NMR (DMSO-d₆, 400 MHz): δ 8.81 (d, J = 2.4 Hz, 1H), 8.69 (s, 1H),8.53 (s, 1H), 7.67 (t, J = 8.8 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 4.31(t, J = 8.3 Hz, 1H), 3.94-4.06 (m, 3H), 3.89 (s, 3H), 3.67- 3.75 (m,1H), 1.64-1.73 (m, 2H), 1.27- 1.36 (m, 1H), 1.15-1.25 (m, 1H), 0.98 (t,J = 7.3 Hz, 3H). LCMS m/z = 347 [MH]⁺. RT [Analytical SFC Method C] =4.40 min. 217

¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (s, 1H), 8.54 (t, J = 2.0 Hz, 1H),8.48 (d, J = 2.5 Hz, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.24 (t, J = 8.8 Hz,1H), 6.98-7.02 (m, 1H), 4.25-4.31 (m, 1H), 4.14 (q, J = 6.9 Hz, 2H),3.81-3.87 (m, 4H), 3.46-3.56 (m, 1H), 1.38 (t, J = 6.8 Hz, 3H), 1.32(dd, J = 8.3, 16.3 Hz, 1H), 1.10 (dd, J = 10.0, 16.1 Hz, 1H). LCMS m/z =332 [MH]⁺. 218

¹H NMR (DMSO-d₆, 400 MHz): δ 8.69 (s, 1H), 8.37 (d, J = 2.0 Hz, 1H),7.69 (m, 1H), 7.54-7.56 (m, 1H), 7.27-7.33 (m, 1H), 4.23-4.27 (m, 1H),3.98-4.01 (m, 2H), 3.91 (s, 3H), 3.78-3.83 (m, 1H), 3.43-3.49 (m, 1H),2.41 (s, 3H), 1.72- 1.77 (m, 2H), 1.26-1.30 (m, 1H), 1.07- 1.11 (m, 1H),0.96-1.00 (m, 3H). LCMS m/z = 343 [MH]⁺. 219

¹H NMR (DMSO-d₆, 400 MHz): δ 8.69 (s, 1H), 8.37 (d, J = 2.0 Hz, 1H),7.69 (m, 1H), 7.54-7.56 (m, 1H), 7.27-7.33 (m, 1H), 4.23-4.27 (m, 1H),3.98-4.01 (m, 2H), 3.91 (s, 3H), 3.78-3.83 (m, 1H), 3.43-3.49 (m, 1H),2.41 (s, 3H), 1.72- 1.77 (m, 2H), 1.26-1.30 (m, 1H), 1.07- 1.11 (m, 1H),0.96-1.00 (m, 3H). LCMS m/z = 343 [MH]⁺. RT [Analytical SFC Method Z] =2.28 min. [α]²⁰ _(D) −16.2 (c = 0.1, EtOH). 220

¹H NMR (MeOD-d₃, 400 MHz): δ 7.85 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H),7.67 (dd, J = 2.0, 8.3 Hz, 1H), 7.39 (s, 1H), 7.06 (d, J = 8.8 Hz, 1H),4.17 (q, J = 7.2 Hz, 3H), 4.02 (br s, 1H), 3.89 (s, 3H), 3.57 (br s,1H), 1.45 (t, J = 7.1 Hz, 3H), 1.33-1.41 (m, 1H), 1.24-1.32 (m, 1H).LCMS m/z 382 [MH]⁺. 221

¹H NMR (DMSO-d₆, 400 MHz): δ 8.72 (d, J = 2.8 Hz, 2H), 8.43 (d, J = 2.0Hz, 1H), 7.95 (t, J = 2.0 Hz, 1H), 7.25-7.29 (m, 1H), 7.06 (d, J = 8.4Hz, 2H), 4.28 (t, J = 4.28 Hz, 1H), 3.84-3.88 (m, 4H), 3.80 (s, 3H),3.46-3.54 (m, 1H), 1.28-1.34 (m, 1H), 1.12-1.18 (m, 1H). LCMS m/z = 300[MH]⁺. RT [Analytical SFC Method FA] = 6.04 min. 222

¹H NMR (DMSO-d₆, 400 MHz): δ 8.66 (s, 1H), 7.93-7.99 (m, 2H), 7.05 (d, J= 8.5 Hz, 1H), 6.59 (s, 1H), 4.47 (q, J = 6.9 Hz, 2H), 4.25 (t, J= 8.0Hz, 1H), 4.09 (q, J = 6.9 Hz, 2H), 3.91-3.98 (m, 1H), 3.82 (s, 3H), 3.48(br s, 1H), 1.36 (t, J = 7.0 Hz, 6H), 1.19-1.28 (m, 1H), 1.09-1.18 (m,1H). LCMS m/z [Analytical SFC Method FA] = 359 [MH]⁺. 223

¹H NMR (DMSO-d₆, 400 MHz): δ 8.66 (s, 1H), 7.93-7.99 (m, 2H), 7.05 (d, J= 8.5 Hz, 1H), 6.59 (s, 1H), 4.47 (q, J = 6.9 Hz, 2H), 4.25 (t, J = 8.0Hz, 1H), 4.09 (q, J = 6.9 Hz, 2H), 3.91-3.98 (m, 1H), 3.82 (s, 3H), 3.48(br s, 1H), 1.36 (t, J = 7.0 Hz, 6H), 1.19-1.28 (m, 1H), 1.09-1.18 (m,1H). LCMS m/z = 359 [MH]⁺. RT [Analytical SFC Method D] = 2.97 min. 224

¹H NMR (DMSO-d₆, 400 MHz): δ 8.69 (s, 1H), 7.98 (dd, J = 2.0, 8.5 Hz,1H), 7.94- 7.97 (m, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.63 (s, 1H), 4.26(dd, J = 7.5, 9.0 Hz, 1H), 3.97-4.03 (m, 5H), 3.94 (dd, J = 6.0, 9.0 Hz,1H), 3.82 (s, 3H), 3.50 (d, J = 8.0 Hz, 1H), 1.72-1.81 (m, 2H),1.20-1.27 (m, 1H), 1.10-1.17 (m, 1H), 1.00 (t, J = 7.5 Hz, 3H). LCMS m/z= 359 [MH]⁺. 225

¹H NMR (DMSO-d₆, 400 MHz): δ 8.69 (s, 1H), 7.98 (dd, J = 2.0, 8.5 Hz,1H), 7.94- 7.97 (m, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.63 (s, 1H), 4.26(dd, J = 7.5, 9.0 Hz, 1H), 3.97-4.03 (m, 5H), 3.94 (dd, J = 6.0, 9.0 Hz,1H), 3.82 (s, 3H), 3.50 (d, J = 8.0 Hz, 1H), 1.72-1.81 (m, 2H),1.20-1.27 (m, 1H), 1.10-1.17 (m, 1H), 1.00 (t, J = 7.5 Hz, 3H). LCMS m/z= 359 [MH]⁺. [α]²⁰ _(D) −16.9 (c = 0.1, EtOH). 226

¹H NMR (DMSO-d₆, 400 MHz): δ 8.57 (s, 1H), 7.81-7.88 (m, 1H), 7.59 (d, J= 7.8 Hz, 1H), 7.49-7.55 (m, 1H), 7.42-7.48 (m, 1H), 7.32 (d, J = 7.6Hz, 1H), 5.11 (t, J = 5.1 Hz, 1H), 4.27 (t, J = 8.3 Hz, 1H), 4.08 (t, J= 8.7 Hz, 1H), 3.91 (s, 3H), 3.59- 3.68 (m, 1H), 1.79-1.93 (m, 4H),1.68- 1.76 ( m, 2H), 1.54-1.63 (m, 2H), 1.28- 1.36 (m, 1H), 1.21-1.28(m, 1H). LCMS m/z = 379 [MH]⁺. 227

¹H NMR (DMSO-d₆, 400 MHz): δ = 8.85 (s, 1H), 8.65 (d, J = 5.2 Hz, 1H),7.97 (s, 1H), 7.73-7.74 (m, 2H), 7.43 (d, J = 4.8 Hz, 1H), 7.06 (d, J =4.8 Hz, 1H), 6.58 (s, 1H), 5.00 (d, J = 1.6 Hz, 1H), 3.86 (m, 3H), 3.82(s, 3H). LCMS m/z = 298 [MH]⁺. 228

1H NMR (CD₃OD, 400 MHz): δ 8.60 (br s, 1H), 8.37 (br s, 1H), 7.93 (s,1H), 7.22- 7.30 (m, 2H), 7.10 (d, J = 8.3 Hz, 1H), 4.16 (t, J = 4.6 Hz,2H), 4.08 (br s, 1H), 3.83-3.95 (m, 6H), 3.34-3.42 (m, 1H), 1.25-1.39(m, 2H). LCMS m/z = 330 [MH]⁺. [α]²⁰ _(D) +31.9 (c = 0.1, EtOH). 229

¹H NMR (DMSO-d₆, 400 MHz): δ 8.85 (d, J = 2.0 Hz, 1H), 8.77 (s, 1H),8.73 (d, J = 2.0 Hz, 1H), 8.13 (s, 1H), 7.31-7.33 (m, 2H), 7.07 (d, J =8.0 Hz, 1H), 6.45 (s, 1H), 5.01 (s, 2H), 4.14 (q, J = 6.8 Hz, 2H), 3.81(s, 3H), 1.36 (q, J = 6.8 Hz, 3H). LCMS m/z = 312 [MH]⁺. 230

¹H NMR (DMSO-d₆, 400 MHz): δ 8.64 (br s, 1H), 7.84 (dd, J = 3.4, 8.8 Hz,1H), 7.67 (t, J = 4.6 Hz, 2H), 7.60 (dd, J = 1.5, 8.3 Hz, 1H), 7.03 (d,J = 8.8 Hz, 1H), 4.27 (t, J = 7.8 Hz, 1H), 3.98-4.07 (m, 3H), 3.85 (d, J= 6.8 Hz, 1H), 3.81 (s, 3H), 1.72-1.80 (m, 2H), 1.22-1.27 (m, 2H), 1.00(t, J = 7.3 Hz, 3H). LCMS m/z = 346 [MH]⁺. RT [Analytical SFC Method G]= 3.25 min. 231

¹H NMR (DMSO-d₆, 400 MHz): δ 8.67 (s, 1H), 8.34 (s, 1H), 7.65 (s, 1H),7.37 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 4.21-4.28 (m, 3H),3.76-3.85 (m, 4H), 3.41-3.50 (m, 1H), 2.52 (s, 3H), 1.70- 1.78 (m, 2H),1.29 (dd, J = 8.2, 16.3 Hz, 1H), 1.06 (dd, J = 10.0, 16.1 Hz, 1H), 0.95(t, J = 7.5 Hz, 3H). LCMS m/z = 343 [MH]⁺. [α]²⁰ _(D) −20.1 (c = 0.1,EtOH). 232

¹H NMR (DMSO-d₆, 400 MHz): δ 7.51 (s, 1H), 7.45 (br d, J = 7.6 Hz, 1H),7.34- 7.35 (m, 1H), 7.16-7.23 (m, 3H), 7.02 (d, J = 8.0 Hz, 1H),4.22-4.28 (m, 1H), 3.84 (s, 3H), 3.81 (s, 1H), 3.79 (s, 3H), 3.42- 3.51(m, 1H), 1.25-1.31 (m, 1H), 1.05- 1.12 (m, 1H). LCMS m/z = 299 [MH]⁺.Example 233

¹H NMR (DMSO-d₆, 400 MHz): δ 8.57 (s, 1H), 7.61-7.70 (m, 3H), 7.59 (d, J= 2.0 Hz, 1H), 7.11-7.13 (m, 1H), 7.00 (d, J = 8.4 Hz, 1H), 4.23-4.28(m, 1H), 4.07-4.09 (m, 2H), 3.92-3.96 (m, 1H), 3.78 (s, 3H), 3.56-3.58(m, 1H), 1.33 (t, J = 7.0 Hz, 3H), 1.16-1.24 (m, 2H). LCMS m/z = 314[MH]⁺.

Single Crystal X-Ray Analysis of crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 3)

The crystal structure of Example 3 was determined by single crystalX-ray diffraction analysis. The single crystal X-ray diffraction datacollection was performed on a Bruker D8 Quest diffractometer at roomtemperature. Data collection consisted of omega and phi scans. Thestructure was solved by intrinsic phasing using SHELX software suite inthe Monoclinic class space group P2₁. The structure was subsequentlyrefined by the full-matrix least squares method. All non-hydrogen atomswere found and refined using anisotropic displacement parameters. Thehydrogen atoms located on oxygen were found from the Fourier differencemap and refined with distances restrained. The remaining hydrogen atomswere placed in calculated positions and were allowed to ride on theircarrier atoms. The final refinement included isotropic displacementparameters for all hydrogen atoms. Analysis of the absolute structureusing likelihood methods (Hooft 2008) was performed using PLATON (Spek2010). The Hooft parameter is reported as 0.02 with an Esd of 0.003 andthe Parson's parameter is reported as 0.02 with an Esd of 0.003. Thefinal R-index was 4.5%. A final difference Fourier revealed no missingor misplaced electron density.

FIG. 1 is the obtained X-ray structure (ORTEP drawing) of crystalline(R) 4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 3). The crystal structure data is summarized in Table 3.

TABLE 3 Crystal data and structure refinement for Example 3 Empiricalformula C₁₇H₂₀BNO₄ Formula weight  313.15 Temperature 296(2) KWavelength 1.54178 Å Crystal system Monoclinic Space group P2₁ Unit celldimensions a = 11.0798(5) Å α = 90°. b = 13.1083(6) Å β = 99.346(2)°. c= 11.2398(6) Å γ = 90°. Volume 1610.77(13) Å³ Z   4 Density (calculated)1.291 Mg/m³ Absorption coefficient 0.738 mm⁻¹ F(000)  664 Crystal size0.360 × 0.220 × 0.140 mm³ Theta range for data collection 3.986 to70.310° Index ranges −13 <= h <= 13, −16 <= k <= 15, −13 <= l <= 12Reflections collected 29459 Independent reflections 6084 [R(int) =0.0304] Completeness to theta = 67.679° 99.9% Absorption correctionEmpirical Refinement method Full-matrix least-squares on F²Data/restraints/parameters 6084/3/426 Goodness-of-fit on F²   1.132Final R indices [I > 2sigma(I)] R1 = 0.0446, wR2 = 0.1005 R indices (alldata) R1 = 0.0452, wR2 = 0.1013 Absolute structure parameter 0.02(3)Extinction coefficient 0.125(4) Largest diff. peak and hole 0.307 and−0.371 e · Å⁻³

Single Crystal X-Ray Analysis of crystalline (R)4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 4)

The crystal structure of Example 4 was determined by single crystalX-ray diffraction analysis. The single crystal X-ray diffraction datacollection was performed on a Bruker D8 Venture diffractometer at −150°C. temperature. Data collection consisted of omega and phi scans. Thestructure was solved by intrinsic phasing using SHELX software suite inthe Monoclinic class space group P2₁. The structure was subsequentlyrefined by the full-matrix least squares method. All non-hydrogen atomswere found and refined using anisotropic displacement parameters. Thehydrogen atoms located on oxygen were found from the Fourier differencemap and refined with distances restrained. The remaining hydrogen atomswere placed in calculated positions and were allowed to ride on theircarrier atoms. The final refinement included isotropic displacementparameters for all hydrogen atoms. Analysis of the absolute structureusing likelihood methods (Hooft 2008) was performed using PLATON (Spek2010). The Hooft parameter is reported as 0.08 with an Esd of 0.003 andthe Parson's parameter is reported as 0.15 with an Esd of 0.002. Thefinal R-index was 4.6%. A final difference Fourier revealed no missingor misplaced electron density.

FIG. 2 is the obtained X-ray structure (ORTEP drawing) of crystalline(R) 4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 4). The crystal structure data is summarized in Table 4.

TABLE 4 Crystal data and structure refinement for Example 4. Empiricalformula C₁₈H₂₂BNO₄ Formula weight  327.17 Temperature 123(2) KWavelength 1.54178 Å Crystal system Monoclinic Space group P2₁ Unit celldimensions a = 10.7077(14) Å α = 90°. b = 13.4140(17) Å β = 110.396(5)°.c = 13.0151(16) Å γ = 90°. Volume 1752.2(4) Å³ Z   4 Density(calculated) 1.240 Mg/m³ Absorption coefficient 0.699 mm⁻¹ F(000)  696Crystal size 0.240 × 0.160 × 0.120 mm³ Theta range for data collection3.623 to 72.240° Index ranges −12 <= h <= 13, −16 <= k <= 16, −16 <= l<= 16 Reflections collected 63647 Independent reflections 6737 [R(int) =0.0312] Completeness to theta = 67.679° 98.8% Absorption correctionEmpirical Refinement method Full-matrix least-squares on F²Data/restraints/parameters 6737/3/443 Goodness-of-fit on F²   1.044Final R indices [I > 2sigma(I)] R1 = 0.0457, wR2 = 0.1282 R indices (alldata) R1 = 0.0477, wR2 = 0.1311 Absolute structure parameter 0.08(3)Extinction coefficient n/a Largest diff. peak and hole 0.279 and −0.203e · Å⁻³

Single Crystal X-Ray Analysis of crystalline (S)4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 5)

The crystal structure of Example 5 was also determined by single crystalX-ray diffraction analysis. The single crystal X-ray diffraction datacollection was performed on a Bruker D8 Quest diffractometer at roomtemperature. Data collection consisted of omega and phi scans. Thestructure was solved by intrinsic phasing using SHELX software suite inthe Monoclinic space group P2₁. The structure was subsequently refinedby the full-matrix least squares method. All non-hydrogen atoms werefound and refined using anisotropic displacement parameters. Thehydrogen atoms located on oxygen were found from the Fourier differencemap and refined with distances restrained. The remaining hydrogen atomswere placed in calculated positions and were allowed to ride on theircarrier atoms. The final refinement included isotropic displacementparameters for all hydrogen atoms. Analysis of the absolute structureusing likelihood methods (Hooft 2008) was performed using PLATON (Spek2010). The Hooft parameter is reported as 0.01 with an Esd of 0.007 andthe Parson's parameter is reported as 0.01 with an Esd of 0.006. Thefinal R-index was 4.8%. A final difference Fourier revealed no missingor misplaced electron density.

FIG. 3 is the obtained X-ray structure (ORTEP drawing) of crystalline(S) 4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 5). The crystal structure data is summarized in Table 5.

TABLE 5 Crystal data and structure refinement for Example 5 Empiricalformula C₁₈H₂₂BNO₄ Formula weight  327.17 Temperature 296(2) KWavelength 1.54178 Å Crystal system Monoclinic Space group P2₁ Unit celldimensions a = 10.6918(4) Å α = 90°. b = 13.4115(4) Å β = 110.311(2)°. c= 13.0161(4) Å γ = 90°. Volume 1750.37(10) Å³ Z   4 Density (calculated)1.242 Mg/m³ Absorption coefficient 0.700 mm⁻¹ F(000)  696 Crystal size0.260 × 0.220 × 0.140 mm³ Theta range for data collection 3.621 to70.234° Index ranges −12 <= h <= 13, −16 <= k <= 16, −15 <= l <= 15Reflections collected 16854 Independent reflections 6536 [R(int) =0.0328] Completeness to theta = 67.679° 99.3% Absorption correctionEmpirical Refinement method Full-matrix least-squares on F²Data/restraints/parameters 6536/3/446 Goodness-of-fit on F²   1.065Final R indices [I > 2sigma(I)] R1 = 0.0478, wR2 = 0.1176 R indices (alldata) R1 = 0.0512, wR2 = 0.1220 Absolute structure parameter 0.01(7)Extinction coefficient 0.0385(19) Largest diff. peak and hole 0.236 and−0.273 e · Å⁻³

Single Crystal X-Ray Analysis of crystalline (R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol(Example 19)

The crystal structure of Example 19 was also determined by singlecrystal X-ray diffraction analysis. The single crystal X-ray diffractiondata collection was performed on a Bruker D8 Quest diffractometer atroom temperature. Data collection consisted of omega and phi scans. Thestructure was solved by intrinsic phasing using SHELX software suite inthe Monoclinic class space group P2₁. The structure was subsequentlyrefined by the full-matrix least squares method. All non-hydrogen atomswere found and refined using anisotropic displacement parameters. Thehydrogen atoms located on oxygen were found from the Fourier differencemap and refined with distances restrained. The remaining hydrogen atomswere placed in calculated positions and were allowed to ride on theircarrier atoms. The final refinement included isotropic displacementparameters for all hydrogen atoms. Analysis of the absolute structureusing likelihood methods (Hooft 2008) was performed using PLATON (Spek2010). The Hooft parameter is reported as 0.06 with an Esd of 0.004 andthe Parson's parameter is reported as 0.06 with an Esd of 0.003. Thefinal R-index was 4.0%. A final difference Fourier revealed no missingor misplaced electron density.

FIG. 4 is the obtained X-ray structure (ORTEP drawing) of crystalline(R)4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol(Example 19). The crystal structure data is summarized in Table 6.

TABLE 6 Crystal data and structure refinement for Example 19 Empiricalformula C₃₆H₄₄B₂N₂O₈ Formula weight  654.35 Temperature 296(2) KWavelength 1.54178 Å Crystal system Monoclinic Space group P2₁ Unit celldimensions a = 11.2655(18) Å α = 90°. b = 12.903(2) Å β = 111.269(5)°. c= 12.959(2) Å γ = 90°. Volume 1755.4(5) Å³ Z   2 Density (calculated)1.238 Mg/m³ Absorption coefficient 0.698 mm⁻¹ F(000)  696 Crystal size0.420 × 0.360 × 0.120 mm³ Theta range for data collection 3.660 to72.747° Index ranges −13 <= h <= 13, −15 <= k <= 15, −15 <= l <= 16Reflections collected 53020 Independent reflections 6907 [R(int) =0.0361] Completeness to theta = 67.679° 100.0% Absorption correctionEmpirical Refinement method Full-matrix least-squares on F²Data/restraints/parameters 6907/3/446 Goodness-of-fit on F²   1.055Final R indices [I > 2sigma(I)] R1 = 0.0396, wR2 = 0.1023 R indices (alldata) R1 = 0.0414, wR2 = 0.1043 Absolute structure parameter 0.06(4)Extinction coefficient 0.0261(13) Largest diff. peak and hole 0.230 and−0.298 e · Å⁻³

X-Ray Powder Diffraction

The crystal structures of Examples 3, 4, 5, 10 and 19 were analyzedusing X-ray powder diffraction (“PXRD”).

For Example 4, powder X-ray diffraction analysis was conducted using aBruker AXS D8 ADVANCE diffractometer equipped with a Cu radiation source(K-α average). The system is equipped with a 2.5 axial Soller slits onthe primary side. The secondary side utilizes 2.5 axial Soller slits andmotorized slits. Diffracted radiation was detected by a Lynx Eye XEdetector. The X-ray tube voltage and amperage were set to 40 kV and 40mA respectively. Data was collected in the Theta-Theta goniometer at theCu wavelength from 3.0 to 40.0 degrees 2-Theta using a step size of0.037 degrees and a step time of 10 seconds per step. Samples wereprepared by placing them in a low background holder (Bruker part number:C79298A3244B261) and rotated during collection. Data were collectedusing Bruker DIFFRAC Plus software. Analysis performed by EVA diffractplus software. The PXRD data file was not processed prior to peaksearching. Using the peak search algorithm in the EVA software, peaksselected with a threshold value of 1 and a width of 0.3 were used tomake preliminary peak assignments. To ensure validity, adjustments weremanually made; the output of automated assignments was visually checkedand peak positions were adjusted to the peak maximum. Peaks withrelative intensity of ≥3% were generally chosen. The peaks which werenot resolved or were consistent with noise were not selected. A typicalerror associated with the peak position from PXRD stated in USP up to+/−0.2° 2-Theta (USP-941).

For Examples 3, 5, 10, and 19, powder X-ray diffraction analysis wasconducted using a Bruker AXS D4 Endeavor diffractometer equipped with aCu radiation source (K-α average). The system is equipped with a 2.5axial Soller slits on the primary side. The secondary side utilizes 2.5axial Soller slits and motorized slits. Diffracted radiation wasdetected by a Lynx Eye XE detector. The X-ray tube voltage and amperagewere set to 40 kV and 40 mA respectively. Data was collected in theTheta-2Theta goniometer at the Cu wavelength from 3.0 to 43.0 degrees2-Theta using a step size of 0.020 degrees and a step time of 3 secondsper step. Samples were prepared by placing them in a low backgroundholder and rotated during collection. Data were collected using BrukerDIFFRAC Plus software. Analysis performed by EVA diffract plus software.The PXRD data file was not processed prior to peak searching. Using thepeak search algorithm in the EVA software, peaks selected with athreshold value of 1 and a width of 0.3 were used to make preliminarypeak assignments. To ensure validity, adjustments were manually made;the output of automated assignments was visually checked and peakpositions were adjusted to the peak maximum. Peaks with relativeintensity of ≥3% were generally chosen. The peaks which were notresolved or were consistent with noise were not selected. A typicalerror associated with the peak position from PXRD stated in USP up to+/−0.2° 2-Theta (USP-941).

As will be appreciated by the skilled crystallographer, the relativeintensities of the various peaks reported in the Tables and Figuresbelow may vary due to a number of factors such as orientation effects ofcrystals in the X-ray beam or the purity of the material being analyzedor the degree of crystallinity of the sample. The peak positions willremain substantially as defined. The skilled crystallographer also willappreciate that measurements using a different wavelength will result indifferent shifts according to the Bragg equation −nλ=2d sin θ. Suchfurther PXRD patterns of the crystalline materials of the presentinvention and as such are within the scope of the present information.

FIG. 5 is the obtained powder X-ray diffraction pattern for crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 3) and Table 7 lists the PXRD peaks.

TABLE 7 Example 3 PXRD Data Angle 2-Theta (Degrees) Rel. Intensity %10.5 87.7 12.3 19.2 13.5 10.1 15.8 10.6 16.0 15.9 16.2 6.0 17.3 2.8 18.371.9 20.4 3.8 21.0 7.9 21.1 7.0 21.5 63.0 22.9 27.1 23.8 6.4 24.4 67.224.9 100.0 25.4 23.3 25.6 14.4 26.5 10.8 27.8 17.4 28.4 6.2 29.2 3.330.2 10.2 32.1 3.2 33.5 5.3 33.8 3.0 34.5 4.4 37.7 4.7 40.5 6.4 41.3 3.5

FIG. 6 is the obtained powder X-ray diffraction pattern for crystalline(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 4) and Table 8 lists the PXRD peaks.

TABLE 8 Example 4 PXRD Data Angle (2-Theta) Degrees Rel. Intensity %11.0 94.9 11.4 64.8 13.2 43.1 14.5 27.3 15.1 39.3 15.6 23.1 15.9 9.417.7 10.0 18.8 81.8 19.4 13.0 19.7 49.3 20.5 12.4 21.3 45.1 22.0 8.522.9 100.0 23.8 5.7 24.5 6.0 25.1 71.8 25.6 4.6 25.9 20.5 26.4 36.0 27.517.1 28.4 8.9 28.8 4.9 30.4 3.6

FIG. 7 is the obtained powder X-ray diffraction pattern for crystalline(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 5) and Table 9 lists the PXRD peaks.

TABLE 9 Example 5 PXRD Data Angle (2-Theta) Degrees Rel. Intensity %11.0 60.0 11.4 44.8 13.2 28.3 14.5 18.6 15.1 27.2 15.6 16.5 15.9 6.917.7 7.2 18.7 67.4 19.4 10.4 19.7 42.6 20.5 10.8 21.2 40.4 21.9 8.1 22.14.3 22.8 100.0 23.8 5.7 24.4 6.3 25.0 67.0 25.5 5.0 25.9 19.98 26.4 33.927.4 18.8 28.3 10.5 28.8 5.7 30.0 3.5 30.4 4.1 32.1 3.5 35.5 3.4 36.14.1 38.0 3.7 38.5 3.3 39.0 3.1 39.6 3.3 41.4 3.9

FIG. 8 is the obtained powder X-ray diffraction pattern for crystalline(−)4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol(Example 10) and Table 10 lists the PXRD peaks.

TABLE 10 Example 10 PXRD Data Angle 2-Theta (Degrees) Rel. Intensity %8.9 12.7 12.0 18.0 12.3 14.5 12.8 100.0 13.7 5.6 13.9 20.6 14.2 13.214.5 3.7 15.9 5.8 17.6 14.4 17.8 31.5 19.2 21.6 19.4 16.5 19.6 17.2 20.459.3 21.4 13.9 22.0 16.3 22.3 17.4 22.5 15.1 22.9 32.3 23.1 31.4 24.214.5 25.7 44.2 27.3 3.7 27.5 6.3 28.5 11.7 28.8 7.0 29.6 5.2 30.7 12.933.7 3.9 35.6 9.9 40.3 3.7 40.9 5.4

FIG. 9 is the obtained powder X-ray diffraction pattern for crystalline(R)-4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-ol(Example 19) and Table 11 lists the PXRD peaks.

TABLE 11 Example 19 PXRD Data Angle 2-Theta (Degrees) Rel. Intensity %10.1 4.9 10.9 65.9 11.3 23.2 13.1 4.3 13.7 3.9 14.7 7.5 17.0 14.7 17.333.4 19.0 32.4 19.3 59.2 19.7 17.8 19.7 23.6 20.2 4.5 20.6 7.4 21.1 59.021.9 5.8 22.7 85.5 23.6 14.1 23.8 100.0 23.9 61.7 24.1 10.6 24.5 6.624.8 18.8 25.4 47.8 25.4 38.6 26.2 6.4 26.5 13.9 26.8 3.6 27.1 15.4 27.111.8 27.5 10.1 28.5 3.8 28.5 5.8 29.5 3.1 30.4 28.8 30.5 16.9 32.2 4.934.2 4.0 35.9 3.5 39.1 5.4 39.5 3.8 39.9 5.0 40.9 4.2 42.2 7.1

Formulation Examples

An embodiment of the present invention provides a topical pharmaceuticalformulation comprising: (a) an active agent of the invention whichtreats an inflammatory related condition, or a pharmaceuticallyacceptable salt, or a hydrate or a solvate thereof, (b) from about 5%(w/w) to about 15% (w/w) solvent, and (c) an ointment base. In anembodiment, the present invention provides a topical pharmaceuticalformulation comprising: (a) an active agent of the invention whichtreats an inflammatory related condition, or a pharmaceuticallyacceptable salt, or a hydrate or a solvate thereof, (b) from about 5%(w/w) to about 15% (w/w) solvent, and (c) petrolatum. In an embodiment,the present invention provides a topical pharmaceutical formulationcomprising: (a) an active agent of the invention which treats aninflammatory related condition, or a pharmaceutically acceptable salt,or a hydrate or a solvate thereof, (b) from about 5% (w/w) to about 15%(w/w) solvent, (c) ointment, (d) an antioxidant, (e) a stabilizer, (f)an emulsifying agent, and (g) a stiffening agent. In an embodiment, thepresent invention provides a topical pharmaceutical formulationcomprising: (a) an active agent of the invention which treats aninflammatory related condition, or a pharmaceutically acceptable salt,or a hydrate or a solvate thereof, (b) from about 5% (w/w) to about 15%(w/w) solvent, (c) ointment, (d) an antioxidant, (e) an emulsifyingagent, and (f) a stiffening agent. In an embodiment, the presentinvention provides a topical pharmaceutical formulation comprising: (a)an active agent of the invention which treats an inflammatory relatedcondition, or a pharmaceutically acceptable salt, or a hydrate or asolvate thereof, (b) from about 5% (w/w) to about 15% (w/w) solvent, (c)petrolatum, (d) an antioxidant, (e) an emulsifying agent, and (f) astiffening agent. In an embodiment, the present invention provides atopical pharmaceutical formulation comprising: (a) an active agent ofthe invention which treats an inflammatory related condition, or apharmaceutically acceptable salt, or a hydrate or a solvate thereof, (b)from about 8% (w/w) to about 10% (w/w) propylene or hexylene glycol, (c)from about 75% (w/w) to about 80% (w/w) white petrolatum, (d) from about8% (w/w) to about 10% of a glyceride blend, (e) from about 4% to about6% paraffin, and (f) from about 0.05% to 0.5% butylated hydroxytoluene.In an embodiment, the present invention provides a topicalpharmaceutical formulation comprising: (a) an active agent of theinvention which treats an inflammatory related condition, or apharmaceutically acceptable salt, or a hydrate or a solvate thereof, (b)from about 8% (w/w) to about 10% (w/w) hexylene glycol, (c) from about75% (w/w) to about 80% (w/w) white petrolatum, (d) from about 8% (w/w)to about 10% of a glyceride blend, (e) from about 4% to about 6%paraffin, and (f) from about 0.05% to 0.5% butylated hydroxytoluene.

In an embodiment, the present invention provides a topicalpharmaceutical formulation comprising an active agent wherein “activeagent” is a compound of the present invention or a pharmaceuticallyacceptable salt, hydrate or a solvate thereof. In another embodiment,the active agent is(R)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ora pharmaceutically acceptable salt, hydrate, or solvate thereof. Inanother embodiment, the active agent is(S)-4-(5-(4-methoxy-3-propoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ora pharmaceutically acceptable salt, hydrate, or solvate thereof. Inanother embodiment, the active agent is(R)-4-(5-(3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol ora pharmaceutically acceptable salt, hydrate, or solvate thereof. Inanother embodiment, the active agent is(R)-4-(5-(3-ethoxy-4-methoxyphenyl)-6-methylpyridin-3-yl)-1,2-oxaborolan-2-olor a pharmaceutically acceptable salt, hydrate, or solvate thereof. Inanother embodiment, the active agent is(−)-4-(5-(2-(difluoromethyl)-3-ethoxy-4-methoxyphenyl)pyridin-3-yl)-1,2-oxaborolan-2-ol,or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

In another embodiment, the present invention provides a topicalpharmaceutical formulation comprising an active agent present in aconcentration of about 0.0001% to about 3.0% (w/w). In anotherembodiment, the active agent is present in a concentration of about0.001% to about 2.0% (w/w). In another embodiment, the active agent ispresent in a concentration of about 0.01% to about 1.0% (w/w). Inanother embodiment, the active agent is present in a concentration ofabout 0.05% to about 0.5% (w/w).

In another embodiment, the present invention provides an active agent,or a salt, hydrate or solvate thereof. In another embodiment, thepresent invention provides a combination of an active agent and a secondactive agent wherein the second active agent is useful for the treatmentof inflammatory disorders such as atopic dermatitis, eczema, psoriasis,arthritis, asthma, fibrosis, lupus, allergy, fibromyalgia, woundhealing, and inflammation resulting from surgical complications. Thecombination may be comprised of an admixture or co-formulation of thetwo active ingredients. Alternatively, the combination may be packagedin a dispenser wherein one active agent is in one chamber and anotheractive ingredient is in a second chamber, but upon dispensing, the twoactive agents are simultaneously delivered together such thatadministration of the combination may occur in one application.Alternatively, the active agents may individually be administered withthe other active agent, wherein the second active agent may beadministered either orally or topically.

In another embodiment, the present invention provides an active agentdescribed herein, or a salt, hydrate or solvate thereof, in a topicalformulation which comprises a solvent. In another embodiment, thesolvent is an alkyl glycol or alkyl alcohol. In another embodiment, thesolvent is an alkyl glycol. In another embodiment, the solvent ispropylene glycol. In another embodiment, the solvent is hexylene glycol.In another embodiment, the solvent is butylene glycol. In anotherembodiment, the solvent is present in a concentration of about 5.0%(w/w) to about 15.0% (w/w). In another embodiment, the solvent ispresent in a concentration of about 6.0% (w/w) to about 12.0% (w/w). Inanother embodiment, the solvent is present in a concentration of about7.0% (w/w) to about 11.0% (w/w). In another embodiment, the solvent ispresent in a concentration of about 8.0% (w/w) to about 10.0% (w/w).

In another embodiment, the present invention provides an active agentdescribed herein, or a salt, hydrate or solvate thereof, in a topicalformulation which comprises an ointment base. In another embodiment, theointment base is white petrolatum. In another embodiment, the ointmentbase is mineral jelly, petroleum jelly, yellow petrolatum, yellow softparaffin, yellow petroleum jelly, white petrolatum jelly, or white softparaffin. In another embodiment, the base is mineral oil, light mineraloil, paraffin, or lanolin alcohol. The amount of ointment base in thetopical pharmaceutical formulation will be dependent on the amounts ofthe other components. In another embodiment, the ointment base ispresent in a quantum satis concentration. In another embodiment, theointment base is present in a concentration of from about 65% (w/w) toabout 85% (w/w). In another embodiment, the base is present in aconcentration of from about 70% (w/w) to about 80% (w/w). In anotherembodiment, the base is present in a concentration of from about 75%(w/w) to about 80% (w/w).

In another embodiment, the present invention provides an active agentdescribed herein, or a salt, hydrate or solvate thereof, in a topicalformulation which further comprises an antioxidant. In anotherembodiment, the antioxidant is butylated hydroxytoluene, ascorbic acid,ascorbic palmitate, butylated hydroxyanisole,2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butyl phenol,erythorbic acid, gum guaiac, propyl gallate, thiodipropionic acid,dilauryl thiodipropionate, tert-butylhydroquinone, or tocopherol. Inanother embodiment, the antioxidant is butylated hydroxytoluene. Inanother embodiment, the antioxidant is present in a concentration ofabout 0.01% (w/w) to about 1% (w/w). In another embodiment, theantioxidant is present in a concentration of about 0.01% (w/w) to about0.5% (w/w). In another embodiment, the antioxidant is present in aconcentration of about 0.05% (w/w) to about 0.5% (w/w). In anotherembodiment, the antioxidant is present in a concentration of about0.075% (w/w) to about 0.2% (w/w).

In another embodiment, the topical pharmaceutical formulation furthercomprises an emulsifying agent. In another embodiment, the emulsifyingagent is a glyceride blend. In another embodiment, the emulsifying agentis a glyceride blend, wherein the glyceride blend comprises amonoglyceride and a diglyceride. In another embodiment, the emulsifyingagent is a glyceride blend, wherein the glyceride blend comprises amonoglyceride, a diglyceride, and a triglyceride. In another embodiment,the emulsifying agent is a glyceride blend, wherein the glyceride blendcomprises a monoglyceride and a diglyceride, and wherein from about 40%(w/w) to about 55% (w/w) of the glyceride blend is a monoglyceride. Inanother embodiment, the emulsifying agent is a glyceride blend, whereinthe glyceride blend comprises a monoglyceride, a diglyceride, and atriglyceride, and wherein from about 40% (w/w) to about 55% (w/w) of theglyceride blend is a monoglyceride. In another embodiment, themonoglyceride is selected from the group consisting of glycerylmonostearate, glyceryl monopalmitate, glyceryl monooleate, orcombinations thereof. In another embodiment, the monoglyceride is amonoglyceryl ester of a long chain, saturated or unsaturated fatty acid.In an embodiment, the monoglyceride is an alpha-monoglyceride. In apreferred embodiment, the diglyceride is a diglyceryl ester of a longchain, saturated or unsaturated fatty acid. In another embodiment, theglyceride blend is present in a concentration of about 3.0% (w/w) toabout 10.0% (w/w). In another embodiment, the glyceride blend is presentin a concentration of about 5.0% (w/w) to about 10.0% (w/w). In anotherembodiment, the glyceride blend about 6.0% (w/w) to about 8.0% (w/w).

In another embodiment, the topical pharmaceutical formulation furthercomprises a stiffening agent. In another embodiment, the stiffeningagent is a wax. In another embodiment, the stiffening agent is a wax andthe wax is selected from the group consisting of beeswax, paraffin wax,and spermaceti wax. In another embodiment, the stiffening agent isparaffin wax. In another embodiment, the stiffening agent is present ina concentration of about 3.0% (w/w) to about 7.0% (w/w). In a preferredembodiment, the stiffening agent is present in a concentration of about4.0% (w/w) to about 6.0% (w/w). In another embodiment, the stiffeningagent is present in a concentration of about 4.5% (w/w) to about 5.5%(w/w).

In another embodiment, the topical pharmaceutical formulation furthercomprises a stabilizer. In another embodiment, the stabilizer isethylenediaminetetraacetic acid, or a pharmaceutically acceptable saltthereof. In another embodiment, the stabilizer is a pharmaceuticallyacceptable salt of ethylenediaminetetraacetic acid, and this salt is asodium salt or a potassium salt or a calcium salt, or a combinationthereof. In another embodiment, the stabilizer is present in aconcentration of about 0.000010% (w/w) to about 0.0450% (w/w).

The composition of topical formulations for compounds of the presentinvention include excipients that provide at least one of the followingfunctionalities: solvent; base; dispersing agent; emulsifying agent;stiffening agent; rheology modifying agent; stabilizing agent; andantioxidant. For example, suitable topical ointment formulations forExample 4 include, but are not limited to, the formulations listed inTables 12, 13, 15 and 16. In addition to the ointment formulationslisted in Tables 12 and 13, other topical formulations suitable for thecompounds of the present invention include, but are not limited to,creams, lotions, gels, solutions, suspensions, foams, and sprays.

TABLE 12 Quantity (% w/w) Example 4 0.001-1 0.001-1 0.001-1 0.001-10.001-1 0.001-1 Propylene 2-9 glycol Hexylene 2-9 glycol Transcutol 2-9Diisopropyl  2-20 adipate PEG400 2-9 Propylene 2-9 carbonate White qs qsqs qs qs qs petrolatum Mono- and 0-7 0-7 0-7 0-7 0-7 0-7 diglyceridesSpan 60 0-2 0-2 0-2 0-2 0-2 0-2 Span 40 0-2 0-2 0-2 0-2 0-2 0-2Phospholipid  0-10  0-10  0-10  0-10  0-10  0-10 (lecithin) Butylated 0-0.1  0-0.1  0-0.1  0-0.1  0-0.1  0-0.1 Hydroxy- toluene Butylated 0-0.1  0-0.1  0-0.1  0-0.1  0-0.1  0-0.1 Hydroxy- anisole Paraffin Wax0-5 0-5 0-5 0-5 0-5 0-5 Total (%) 100.0 100.0 100.0 100.0 100.0 100.0*qs or quantum satis means sufficient amount to make the total = 100%

Topical formulations prepared containing Example 4 that were tested forskin permeability and maximum flux of Example 4 are listed in Table 13.

TABLE 13 Quantity (% w/w) Example 4 1 0.1 0.01 0 White 77.9 78.8 78.8978.9 petrolatum, USP Mono- and 7 7 7 7 diglycerides, NF Butylated 0.10.1 0.1 0.1 Hydroxytoluene (BHT), NF/PhEur Paraffin Wax, NF 5 5 5 5Hexylene Glycol, 9 9 9 9 NF/USP Total (%) 100.0 100.0 100.0 100.0

In-vitro skin permeation study or Franz cell assay was used todemonstrate the ability of of the formulations in Table 13 to enableExample 4 permeation across stratum corneum barrier and mobility throughepidermis and dermis by way of flux measurement. The formulationsexhibited a concentration dependent skin flux (Table 14) and mayaccommodate a broad range of Example 4 concentrations, providing a rangeof thermodynamic driving forces for Example 4 to permeate skin. A higherdriving force can be achieved via incorporation into the formulations ofadditional penetration enhancers such as oleyl alcohol.

TABLE 14 Cumulative Amount Permeated and Maximum Flux of Example 4 Mean,Std Error, Example 4 Cumulative Cumulative Formulations Amount in Amountin Mean, Max. Flux, Std Error, Max. Flux, From Table 13 N* 24 hours,(ng) 24 hours (ng) (ng/cm²/hr) (ng/cm²/hr) 1% Example 4 15 3357.7 769.6252.28 49.05 0.1% Example 4 15 1089.9 131.9 73.95 7.53 0.01% Example 415 233.0 23.5 20.14 1.75 0% Example 4 6 0 0 0 0 *Number of skin donor =3; Replicate per donor = 5.

TABLE 15 Quantity (% w/w) Example 4 0.001-1 0.001-1 0.001-1 0.001-1Medium chain triglycerides*  2-20 Crodamol GTCC  2-20 Crodamol GMCC 2-20 Triacetin  2-10 White petrolatum qs qs qs qs Mono- anddiglycerides 0-7 0-7 0-7 0-7 Span 60 0-2 0-2 0-2 0-2 Span 40 0-2 0-2 0-20-2 Phospholipid (lecithin)  0-10  0-10  0-10  0-10 ButylatedHydroxytoluene   0-0.1   0-0.1   0-0.1   0-0.1 Butylated Hydroxyanisole  0-0.1   0-0.1   0-0.1   0-0.1 Paraffin Wax 0-5 0-5 0-5 0-5 Total (%)100.0 100.0 100.0 100.0 *Medium chain triglycerides contain two or threefatty acids having an aliphatic tail of 6-12 carbon atoms.

TABLE 16 Example 4 Topical Ointment Formulations milligrams/grammilligrams/gram milligrams/gram Component (mgs/g) (mgs/g) (mgs/g)Example 4 0.100 0.300 0.600 Hexylene Glycol 90.000 90.000 90.000 WhitePetrolatum 788.900 788.700 788.400 Mono- and Di-Glycerides 70.000 70.00070.000 Paraffin Wax 50.000 50.000 50.000 Butylated Hydroxytoluene (BHT)1.000 1.000 1.000 Total 1000.000 1000.000 1000.000

Biological Assays PDE4 SPA Assay

Phosphodiesterase (PDE) activity is determined by measuring the effectof a test agent on the activity of the PDE4B enzyme in a scintillationproximity assay (SPA). At the time of assay, approximately 30 μL ofPDE4B (aa 152-484, Uniprot ID Q07343) in 50 mM Tris pH 7.5, 1.3 mMMgCl₂, 0.004% Brij 35 is added to a 384 well white clear bottompolystyrene plate (Corning) containing 1 μL of varying concentrations oftest compound. After −10 minutes at room temperature (RT; −21° C.), theassay is initiated by the addition of 20 μL of a mixture of ³H-labeled(adenosine 3′, 5′-cyclic phosphate, ammonium salt, [2,8-³H]; PerkinElmer) and unlabeled cAMP. The final assay conditions are approximately81.6 μM PDE4B in 50 mM Tris pH 7.5, 1.3 mM MgCl₂, 0.004% Brij 35, 1 μM³H-labeled/unlabeled cAMP (1425 dpm/pmol) and the indicated finalconcentration of test compound (approximately 10 μM to 9.5 μM by 4-folddilution). The final concentration of DMSO in the assay is approximately2.0%. After 30 minutes at RT, the assay is terminated by the addition ofapproximately 20 μL of an aqueous solution of PDE YSI SPA beads (8 mg/mLin water; Perkin Elmer). The beads are allowed to settle for at least 2hours and the plate is then counted on a MicroBeta2 (Perkin Elmer). Theconcentrations and resulting effect values for the tested compound areplotted and the concentration of compound required for 50% effect (IC50)is determined with a four-parameter logistic dose response equation(E-WorkBook, ID Business Solutions Ltd.) and shown in Table 17.

Cytokine Assays

Cytokine inhibitory activity is determined by measuring the effect oftest agent on the release of the cytokines IL-4, IL-13 and IFNγ fromhuman peripheral blood mononuclear cells (PBMCs) stimulated with theT-cell mitogen phytohemagglutinin-L (PHA-L). At the time of assay, humanPBMCs (Astarte Biologics) are removed from cryopreservation, thawedquickly at 37° C., diluted in assay medium (RPMI—Gibco 1640 medium, 10%heat inactivated fetal bovine serum (HIFBS), 2 mM glutamine and 10 mMHEPES pH 7.4) and then centrifuged at 250×g for 5 minutes. The resultingcell pellet is re-suspended in assay medium to a concentration ofapproximately 5×10⁶ cells/mL and 50 μL of this cell suspension(approximately 250,000 cells) is added to each well of a 384-well cellculture microtiter plate (Perkin Elmer). Varying concentrations of testcompound are then diluted in assay medium and added to the assay platewells in a volume of 25 μL. After ˜10 minutes at room temperature (21°C.) the cells are stimulated by the addition of 25 μL of PHA-L (14μg/mL; Millipore) and the assay plate is placed in an incubator at 37°C. in a humidified environment in 5% carbon dioxide. The final assayconditions are approximately 250,000 human PBMCs per well in assaymedium containing 3.5 μg/mL PHA-L and the indicated final concentrationof test compound (approximately 10 μM to 9.5 μM by 4-fold dilution). Thefinal concentration of DMSO in the assay is approximately 0.25%. After48 hours, the assay plate is removed from the incubator and centrifugedat 250×g for 5 minutes. A portion of the resulting cell supernatant isthen used to determine the amount of IL-4, IL-13 and IFNγ in each well.Cytokine measurements are made using human IL-4, IL-13 or IFNγ HTRFassay kits (CisBio) following the manufacturer's assay protocol. Theconcentrations and resulting effect values for tested compounds areplotted and the concentration of compound required for 50% effect (IC50)is determined with a four-parameter logistic dose response equation(E-WorkBook, ID Business Solutions Ltd.) and shown in Table 17.

TABLE 17 Example PDE4B2 IL13 IL4 IFNγ number IC₅₀ nM IC₅₀ nM IC₅₀ nMIC₅₀ nM 1 3.16 284 14.34 2.98 2 0.67 1346 210.39 2.73 3 1.14 165 3.540.70 4 0.50 135 4.11 1.06 5 0.93 2394 36.33 4.04 6 1.05 283 17.58 0.72 70.97 289 7.76 0.71 8 2.42 25 0.76 1.20 9 1.26 265 3.63 1.87 10 6.92 4382.39 1.62 11 33.49 10000 141.16 68.33 12 1.08 162 2.32 0.99 13 0.97 1665.98 4.89 14 1.50 91 3.21 1.85 15 1.57 136 1.41 0.71 16 0.05 126 0.540.82 17 0.28 138 0.65 0.47 18 0.74 218 1.91 2.23 19 2.96 1482 2.56 1.6820 26.91 8793 86.83 102.97 21 0.64 159 0.84 1.35 22 7.89 257 1.75 1.4323 0.97 132 0.61 0.85 24 0.99 163 2.24 1.33 25 2.40 2315 67.79 9.17 26399.28 10000 1668.34 3302.07 27 73.39 10000 3786.25 208.88 28 10.85 80131036.85 200.54 29 10.47 3470 9.51 4.82 30 15.54 10000 70.71 11.61 314.20 5726 3.92 2.96 32 12.96 2249 64.00 8.47 33 1.25 181 39.82 1.44 340.52 309 14.34 1.39 35 1.17 230 6.98 1.55 36 0.98 476 5.25 1.27 37 38 391.63 182 13.78 1.82 40 0.37 175 29.25 1.28 41 6.85 397 6.20 1.87 42 0.35205 90.39 1.55 43 8.23 10000 232.92 76.01 44 2.50 167 7.22 1.34 45 2.29450 12.38 3.88 46 3.46 317 11.80 3.77 47 3.01 143 4.11 1.54 48 0.12 2520.82 0.98 49 1.59 166 4.40 3.21 50 0.79 234 1.04 1.52 51 1.27 337 3.731.64 52 9.25 2607 14.59 5.74 53 1.41 115 4.87 0.60 54 7.77 1487 5.584.20 55 2.21 576 3.94 2.27 56 2.81 446 68.04 3.62 57 10.17 239 7.54 2.2958 0.72 103 162.84 1.81 59 60 0.34 308 2.04 0.53 61 0.53 499 0.73 2.1262 0.28 2573 2.66 1.44 63 1.62 312 57.89 2.75 64 18.49 325 8.04 4.44 659.53 814 185.58 5.34 66 2.15 327 86.50 0.71 67 4.02 759 99.92 12.61 680.47 369 4.85 1.50 69 4.39 373 6.51 3.84 70 3.00 890 4.31 2.85 71 11.011908 42.00 18.84 72 0.85 375 102.82 6.21 73 2.19 384 49.87 1.66 74 3.04768 10.91 2.71 75 4.52 395 125.12 5.98 76 10.00 403 5.75 2.17 77 2.40415 40.81 2.61 78 0.55 416 19.09 1.35 79 1.38 748 13.33 0.82 80 1.342153 19.75 4.62 81 2.36 858 54.35 1.62 82 0.55 426 7.14 1.07 83 6.64 4399.42 4.73 84 1.24 444 0.90 0.44 85 0.29 541 0.90 0.56 86 7.26 1334104.66 5.00 87 5.03 444 19.12 3.02 88 2.64 609 63.68 6.14 89 1.21 44926.43 3.50 90 4.33 2793 289.67 13.67 91 3.00 460 5.90 3.92 92 1.79 9473.36 2.70 93 0.50 460 9.87 1.66 94 12.49 606 9.58 3.88 95 4.87 461 7.362.87 96 1.69 965 48.92 5.27 97 3.17 465 34.01 2.81 98 1.13 2800 219.372.67 99 1.37 957 44.33 9.42 100 1.68 472 32.73 4.32 101 2.70 2652 26.0213.33 102 5.85 1236 2.07 3.01 103 1.43 487 0.83 0.76 104 3.58 750 29.415.46 105 3.20 490 14.20 5.46 106 1.83 2085 16.08 3.42 107 2.41 613 27.064.17 108 4.23 493 22.10 4.35 109 4.18 1270 22.69 6.24 110 0.61 496 48.415.10 111 0.97 496 3.01 2.95 112 1.41 588 79.88 8.10 113 1.38 497 36.103.81 114 3.00 2914 32.74 21.49 115 1.10 509 38.43 1.68 116 0.87 50842.02 2.45 117 1.80 520 64.17 10.03 118 0.90 531 9.78 2.65 119 0.72 11885.74 7.34 120 1.11 2089 171.18 7.85 121 0.69 533 57.39 1.50 122 5.63 567362.45 7.49 123 3.11 1635 34.10 3.58 124 2.20 1664 9.48 10.12 125 1.70577 11.31 2.43 126 0.85 680 7.21 0.79 127 5.30 585 62.56 2.84 128 5.74667 53.10 2.25 129 4.04 3337 34.48 24.60 130 1.60 587 120.36 3.21 1318.10 591 11.55 5.70 132 2.63 604 12.95 2.42 133 1.91 628 1.37 1.92 1347.46 1108 1.79 3.04 135 10.31 668 15.32 7.24 136 2.86 670 11.66 2.43 1372.21 1087 37.16 2.52 138 2.04 988 1.08 0.90 139 0.25 788 0.78 0.40 1402.70 3449 3.47 3.20 141 0.95 701 3.35 2.24 142 2.53 1035 4.50 2.04 1432.71 1165 4.11 3.68 144 0.58 706 83.91 5.02 145 6.77 2239 103.33 52.07146 1.21 757 24.35 23.83 147 0.44 1257 2.69 1.57 148 0.24 759 4.92 1.68149 0.49 793 20.22 0.87 150 4.05 827 168.67 18.89 151 5.98 813 39.113.48 152 1.38 828 160.96 6.02 153 3.24 860 50.73 2.57 154 14.13 89331.39 15.18 155 1.81 2602 292.55 5.64 156 0.82 901 127.25 1.56 157 2.96906 189.65 5.62 158 12.04 929 59.12 10.23 159 15.08 931 467.60 25.05 16010.09 2301 25.97 15.92 161 11.26 960 419.00 38.63 162 14.52 975 56.318.29 163 3.71 2512 31.09 14.15 164 5.58 986 41.11 7.87 165 2.11 990127.75 3.25 166 0.97 1006 49.25 5.46 167 1.98 2786 1.37 1.13 168 0.881260 1.17 0.64 169 2.85 2017 32.95 5.84 170 3.78 1069 48.55 2.83 1711.73 1351 2.43 3.22 172 1.76 1112 269.26 27.48 173 10.03 1132 77.0630.17 174 8.57 1137 278.94 14.36 175 5.03 2307 14.32 4.35 176 5.51 11416.51 2.98 177 2.71 1225 154.73 8.49 178 2.02 1284 1.81 0.91 179 0.982730 0.72 0.74 180 3.01 1288 6.33 6.65 181 0.68 1299 2.23 3.17 182 5.141329 245.20 19.59 183 2.72 1367 102.50 6.40 184 0.80 1402 79.25 4.48 1853.38 2984 5.75 1.30 186 4.43 1402 31.42 5.13 187 4.28 1420 41.13 8.84188 12.46 1532 135.44 12.25 189 2.61 1457 7.72 1.46 190 1.43 1476 40.335.01 191 3.84 1502 175.98 4.42 192 2.15 1500 14.63 5.43 193 0.63 152973.11 2.16 194 3.63 1539 2.85 14.71 195 0.72 2190 0.36 0.33 196 0.341543 0.29 0.81 197 22.04 1575 106.85 12.18 198 14.28 1576 14.15 4.85 19910.44 1586 90.38 4.55 200 12.88 1599 128.17 14.09 201 2.13 1661 105.219.51 202 4.29 1668 5.20 8.51 203 14.99 2185 176.06 114.15 204 6.07 170722.71 21.78 205 0.52 1772 1.06 1.09 206 2.65 1793 113.37 27.80 207 10.331802 389.57 53.50 208 0.22 1805 4.06 1.98 209 6.55 1819 308.43 21.72 2101.92 2390 17.58 2.40 211 2.95 1839 27.81 1.83 212 2.27 1895 102.59 3.29213 6.32 1980 80.86 3.36 214 4.92 1995 20.71 13.67 215 2.58 2052 62.712.18 216 4.05 2864 19.63 1.94 217 5.50 2067 20.53 10.33 218 1.45 28363.24 2.30 219 0.82 2130 4.10 1.67 220 3.29 2131 539.65 2.37 221 2.212426 47.35 9.35 222 1.14 2370 1.44 1.17 223 6.67 2689 30.93 22.52 2242.17 2494 8.94 8.12 225 3.79 2376 21.22 4.36 226 8.72 2522 24.68 17.78227 7.94 2541 285.17 9.16 228 6.32 2574 7.78 14.24 229 2.64 2733 194.762.90 230 17.09 2780 140.71 26.53 231 1.98 2954 1.25 1.72 232 4.65 583197.03 17.92 233 8.74 508 103.58 2.94

PDE4B is a major PDE4 isoform in neutrophils and in monocytes, and thePDE4B2 variant is a major subtype found in these cells associated withinflammation. Interferon gamma (IFNγ), interleukin 4 (IL4), andinterleukin 13 (IL13) are cytokines that are primarily produced by Tcells in addition to certain innate immune cell populations. Productionof these cytokines has been associated with inflammatory skin diseases,such as atopic dermatitis and with other immune and inflammatorydiseases. Inhibition of release of these inflammatory cytokines wouldmodulate the inflammatory response.

It is understood that the foregoing detailed description andaccompanying Examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined by theappended claims. Various changes and modifications to the disclosedembodiments will be apparent to those skilled in the art. Such changesand modifications, including without limitation those relating to thechemical structures, substituents, derivatives, intermediates,syntheses, formulations and/or methods of use of the invention, may bemade without departing from the spirit and scope thereof.

Powder X-Ray Diffraction analysis for crystalline(4-methoxy-3-propoxyphenyl)boronic acid,3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine, and3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine.

Powder X-ray diffraction analysis was conducted using a Bruker AXS D8Endeavor diffractometer equipped with a Cu radiation source (K-αaverage). The divergence slit was set at 15 mm continuous illumination.Diffracted radiation was detected by a PSD-Lynx Eye detector, with thedetector PSD opening set at 2.99 degrees. The X-ray tube voltage andamperage were set to 40 kV and 40 mA respectively. Data was collected inthe Theta-Theta goniometer at the Cu wavelength from 3.0 to 40.0 degrees2-Theta using a step size of 0.01 degrees and a step time of 1.0 second.The antiscatter screen was set to a fixed distance of 1.5 mm. Sampleswere rotated at 15 rotations/min during collection. Samples wereprepared by placing them in a silicon low background sample holder androtated during collection. Data were collected using Bruker DIFFRAC Plussoftware and analysis was performed by EVA diffract plus software.

Data analysis was performed by EVA diffract plus software (version4.2.1). The PXRD data file was not processed prior to peak searching.Using the peak search algorithm in the EVA software, peaks selected witha threshold value of 1 were used to make preliminary peak assignments.To ensure validity, adjustments were manually made; the output ofautomated assignments was visually checked and peak positions wereadjusted to the peak maximum. Peaks with relative intensity of ≥3% weregenerally chosen. The peaks which were not resolved or were consistentwith noise were not selected. A typical error associated with the peakposition of crystalline material, from PXRD, stated in USP, is up to+/−0.2° 2-Theta (USP-941).

TABLE 18 PXRD peak list for (4-methoxy-3- propoxyphenyl)boronic acid.

Angle 2-Theta ° Relative Intensity % 8.3 9.2 9.6 19.5 9.9 3.0 10.6 8.112.0 4.9 14.8 100.0 15.4 39.1 16.6 7.9 17.0 7.5 18.3 3.5 18.9 23.7 19.324.6 20.4 3.9 21.1 6.4 21.5 6.5 21.7 7.1 22.0 3.9 23.1 35.9 23.5 73.623.8 32.0 24.5 15.7 25.0 16.5 25.5 39.7 26.2 10.4 27.3 14.4 27.9 22.028.2 17.0 28.5 4.6 29.2 6.8 31.0 12.4 31.3 6.4 31.7 6.1 32.7 4.1 34.44.0 34.7 2.7 35.8 5.4 38.7 5.6 39.3 7.5

TABLE 19 PXRD peak list for3-bromo-5-(4-methoxy-3-propoxyphenyl)pyridine.

Angle 2-Theta ° Relative Intensity % 5.5 100 11.0 5.1 16.4 4.4 21.2 6.622.1 78.7 25.2 11.1 25.3 10.7 26.1 11.6 26.2 6.8 27.7 22 30.0 16.0 30.17.1 30.9 15.9 33.3 14.2 33.4 7.1 39.1 7.7 39.2 3.8

TABLE 20 PXRD peak list for 3-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-2-yl)-5-(4-methoxy-3-propoxyphenyl)pyridine

Angle 2-Theta ° Relative Intensity % 5.5 34.3 7.7 43.6 9.4 8.6 11.0 19.713.4 100.0 15.3 32.2 15.6 2.6 16.3 95.0 18.1 20.9 18.8 92.4 20.5 7.921.0 3.4 21.8 6.2 22.0 17.5 22.5 4.1 23.0 38.0 23.3 5.5 23.6 38.0 23.777.7 23.9 4.6 24.8 2.9 25.5 35.5 26.8 16.5 27.1 3.4 27.5 3.0 28.4 6.728.5 7.9 31.1 4.9 31.3 9.1 31.6 2.8 32.0 5.2 32.8 5.1 33.2 3.4 33.9 8.734.0 11.6 34.1 10.3 35.2 4.3

We claim:
 1. A compound of the structure

or a pharmaceutically acceptable salt thereof.
 2. A compound of thestructure


3. A compound of the structure

wherein the compound is characterized by a powder X-ray diffractionpattern comprising diffraction peaks at angles (2θ) of 11.0° 0 0.2°,22.9°±0.2°, and 25.1°±0.2°.
 4. The compound of claim 3, wherein thecompound is further characterized by a powder X-ray diffraction patterncomprising additional diffraction peaks at angles (2θ) of 11.4°±0.2°,18.8°±0.2°, and 26.4°±0.2°.
 5. The compound of claim 3, wherein thecompound is further characterized by a powder X-ray diffraction patterncomprising additional diffraction peaks at angles (2θ) of 11.4±0.2°,13.2°±0.2°, 18.8°±0.2, 19.7°±0.2°, 21.3±0.2°, 2 and 26.4±0.2°.
 6. Thecompound of claim 3, wherein the compound is further characterized by apowder X-ray diffraction pattern comprising additional diffraction peaksat angles (2θ) of 11.4°±0.2, 13.2°±0.2°, 14.5°±0.2°, 15.1°±0.2°,15.6°±0.2°, 18.8°±0.2°, 19.7°±0.2°, 21.3°±0.2°, and 26.4°±0.2°.
 7. Thecompound of claim 3, wherein the compound is further characterized by apowder X-ray diffraction pattern comprising additional diffraction peaksat angles (2θ) of 11.4°±0.2, 13.2°±0.2°, 14.5°±0.2°, 15.1°±0.2°,15.6°±0.2°, 18.8°±0.2°, 19.4°±0.2°, 19.7°±0.2°, 21.3°±0.2°, 25.9°±0.2°,26.4°±0.2°, and 27.5°±0.2°.
 8. The compound of claim 3, wherein thecompound is further characterized by a powder X-ray diffraction patterncomprising additional diffraction peaks at angles (2θ) of 11.4°±0.2,13.2°±0.2°, 14.5°±0.2°, 15.1°±0.2°, 15.6°±0.2°, 15.9°±0.2°, 17.7°±0.2°,18.8°±0.2°, 19.4°±0.2°, 19.7°±0.2°, 20.5°±0.2°, 21.3°±0.2°, 25.9°±0.2°,26.4°±0.2°, and 27.5°±0.2°.
 9. The compound of claim 3, wherein thecompound is further characterized by a powder X-ray diffraction patterncomprising additional diffraction peaks at angles (2θ) of 11.4°±0.2°,13.2°±0.2°, 14.5°±0.2°, 15.1°±0.2°, 15.6°±0.2°, 15.9°±0.2°, 17.7°±0.2°,18.8°±0.2°, 19.4°±0.2°, 19.7°±0.2°, 20.5°±0.2°, 21.3°±0.2°, 22.0°±0.2°,24.5°±0.2°, 25.9°±0.2°, 26.4°±0.2°, 27.5°±0.2°, and 28.4°±0.2°.
 10. Thecompound of claim 3, wherein the compound is further characterized by apowder X-ray diffraction pattern comprising additional diffraction peaksat angles (2θ) of 11.4°±0.2°, 13.2°±0.2°, 14.5°±0.2°, 15.1°±0.2°,15.6°±0.2°, 15.9°±0.2°, 17.7°±0.2°, 18.8°±0.2°, 19.4°±0.2°, 19.7°±0.2°,2.5°±0.2°, 21.3°±0.2°, 22.0°±0.2°, 23.8°±0.2°, 24.5°±0.2°, 25.6°±0.2°,25.9°±0.2°, 26.4°±0.2°, 27.5°±0.2°, 28.4°±0.2°, 28.8°±0.2°, and30.4°±0.2°.